US9877673B2 - Transdermal sampling and analysis device - Google Patents

Abstract

Transdermal sampling and analysis device, method and system are provided for non-invasively and transdermally obtaining biological samples from a subject and determining levels of analytes of the obtained biological samples. The transdermal sampling and analysis device, method and system may cause disruption to the skin cells to create capillary-like channels from which biological samples may flow to the transdermal sampling and analysis device. The transdermal sampling and analysis device, method and system may collect the biological samples in a reservoir where the biological sample may chemically react with a biologically reactive element. A sensor may convert the produced electrons (ions) into measured electrical signals. The converted signals may be measured and the levels of an analyte may be determined based on the measured signals.

Description

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/421,982 entitled “Transdermal Sampling and Analysis Device,” filed on Dec. 10, 2010, the entire contents of which are hereby incorporated by reference.

BACKGROUND

Effective diagnoses and treatment of diseases depend on accurate monitoring of the current physiological state of a subject. Monitoring the concentration of molecules in the body is an example of a method for determining the physiological state. For example, diabetics must actively monitor their body's glucose levels to treat and prevent potentially life threatening conditions such as hypo- or hyperglycemia.

Monitoring the internal physiological state of a subject requires a two step process. First, biological samples must be obtained from the body of the subject. Second, the sample must be analyzed using any of a variety of methods and systems. Some common methods and systems that may be used to analyze samples obtained from a subject include using assays, sensors and/or biosensors.

Biosensors combine a biological component with a physiochemical detector component to allow for the detection of analytes in biological samples. An analyte is a substance or chemical constituent that is determined in an analytical procedure. For example, glucose is the analyte in the process used in the blood glucose biosensors. Biosensors can be used for detecting or determining characteristics of any kind of analyte that can be analyzed by biological means.

A typical biosensor may include three main parts: i) Biologically reactive elements such as biological materials (e.g., tissues, microorganisms, organelles, cell receptors, enzyme, antibodies, and take acid, etc.), a biologically derived material or biomimic. The sensitive biological elements may be created by biological engineering; ii) a transducer or detector elements which work in a physiochemical way (e.g., optical, piezoelectric, electrochemical, etc.), that may transform the signal resulting from the interaction of the analyte with the biological elements into another signal that can be more easily measured and quantified; and iii) associated electronics or signal processors that are primarily responsible for the display of the results in a user-friendly way.

A common commercial biosensor is the blood glucose biosensor. A blood glucose biosensor may measure current produced by the enzymatic oxidation of glucose in an electrochemical cell. The current generated may be proportional to the concentration of glucose, given that it is the limiting reactant. For this reaction, the enzyme glucose oxidase converts glucose to gluconolactone, releasing electrons in the process. These electrons are transferred to the anode of the electrochemical cell by an electron mediator such as ferricyanide, thus generating a measurable current proportional to the glucose concentration. The generated current is run through an ammeter, then returned through the cathode of the electrochemical cell Biological samples may be obtained using different methods, such as by swabs or transdermally.

Swabbing is a non-invasive method for collecting biological samples from surfaces of the epithelium. This method is used to collect cells or organisms that may be used in testing for genetic traits, monitoring for cancer and detecting the presence of bacteria.

Conventional methods for obtaining biological samples are typically painful and invasive. For example, to determine blood glucose levels, diabetics must draw blood by puncturing or lacerating their skin to draw blood using a sharp instrument. This procedure may be uncomfortable, painful, and especially irritating when it has to be performed multiple times a day in the case of diabetics. In addition to pain and discomfort, there are other undesirable side effects associated with these invasive tissue extraction techniques. For example, diabetics who also suffer from hemophilia face the danger of severe hemorrhage every time they have to test their blood glucose levels using invasive procedures. In another example, these invasive procedures expose immuno-compromised diabetics to increased chances of local or systemic infections.

The currently available biosensors are also designed in a manner to require a relatively large sample to accurately determine analyte concentration. For example, the currently available blood glucose biosensors require at least 300 nl of blood in order to analyze the blood glucose levels. To obtain these larger biological samples, painful and invasive procedures must be employed, which are not desirable.

Therefore, additional research may be required to provide a non-invasive, pain-free procedure which requires a small sample to perform accurate analysis. Transdermal collection of biological samples which permit the non-invasive obtaining of samples from below the epithelial surface are desired. To obtain samples transdermally, the epithelium may be breached without lacerating or puncturing of the skin.

SUMMARY OF THE INVENTION

The various embodiment methods and apparatus allow for a safe and non-invasive transdermal extraction of biological samples using a disruptor unit to generate a localized heat that alters the permeability of the stratum corneum without damaging the stratum corneum. The altered permeability of the stratum corneum allows interstitial fluid to flow and be collected for analysis. The various embodiment methods and apparatus may implement a variety of disruptor configurations, such configurations include variations in the size, shape, and materials used to form the disruptor. Further embodiments may implement channel and reservoir configurations which assist in the delivery of the collected samples to biological reactive elements for sensing of certain properties of the collected samples. In a further embodiment, an applicator unit is disclosed which utilizes disposable transdermal sampling and analysis device unit each having a disruptor unit provided thereon. The applicator unit may include a power supply to apply a voltage (or current) to the disruptor unit in order to generate the localized heat. The applicator unit may also include a display which displays the sensed property values of the biological sample to the user.

The disposable transdermal sampling and analysis device units may be pre-loaded within the applicator unit and disposed of after a pre-determined number of heating cycles. In an alternative embodiment, disposable transdermal sampling and analysis device units may be loaded individually loaded each time the user seeks to replace the transdermal sampling and analysis device. In another embodiment, the applicator unit may communicate sensed property values of the biological sample to a remote computer/server for remote analysis and monitoring.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate exemplary aspects of the invention, and together with the general description given above and the detailed description given below, serve to explain the features of the invention.

FIG. 1 illustrates a cross-sectional view of epithelium layer of human skin.

FIG. 2 illustrates a top view of an embodiment transdermal sampling and analysis device.

FIG. 3 illustrates a top view of an embodiment transdermal sampling and analysis device with a square reservoir.

FIG. 4 illustrates a top view of an embodiment transdermal sampling and analysis device with a trapezoidal shaped reservoir.

FIGS. 5A-5D illustrate top views of embodiment transdermal sampling and analysis devices having different disruptor and reservoir configurations.

FIGS. 6A-6D illustrate top views of embodiment disruptors having different configurations.

FIG. 7 illustrates the measurement of an aspect ratio of a serpentine disruptor.

FIG. 8 illustrates a cross-sectional view of an embodiment disruptor having a serpentine configuration placed on the skin.

FIG. 9 illustrates a top view of a portion of an embodiment transdermal sampling and analysis device including two disruptors.

FIGS. 10A-10E illustrate top views of embodiment transdermal sampling and analysis devices having varying disruptor and reservoir configurations.

FIGS. 11A and 11B illustrate top views of embodiment transdermal sampling and analysis devices having varying channel support configurations.

FIGS. 12A-12C illustrate cross-sectional views of channel supports of embodiment transdermal sampling and analysis devices.

FIG. 13 illustrates a cross-sectional view of the relationship between the disruptor, reservoir and channel support of an embodiment transdermal sampling and analysis device.

FIG. 14A illustrates a top view of a reservoir, sensors and disruptor of an embodiment transdermal sampling and analysis device.

FIG. 14B illustrates a top view of a transdermal sampling and analysis device with the lid according to an embodiment.

FIG. 15A illustrates a top view of a transdermal sampling and analysis device according to an embodiment.

FIGS. 15B and 15C illustrate cross-sectional views of the relationship of different layers the transdermal sampling and analysis device ofFIG. 15A.

FIG. 16 illustrates a perspective view of the raised disruptor of an embodiment transdermal sampling and analysis device.

FIG. 17 is a component block diagram of an embodiment applicator device for applying the transdermal sampling and analysis device.

FIG. 18 is a system component diagram of a transdermal sampling and analysis device system according to an embodiment.

FIG. 19A-19C illustrate embodiment methods for loading an embodiment applicator device with transdermal sampling and analysis devices using different kits.

FIG. 20 illustrates an embodiment method of applying a loaded applicator device to the skin of a subject.

FIG. 21 is a component block diagram of a server suitable for use in the various embodiments.

FIG. 22 is a component block diagram of a computer device suitable for use in the various embodiments.

DETAILED DESCRIPTION

The various embodiments will be described in detail with reference to the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts. References made to particular examples and implementations are for illustrative purposes, and are not intended to limit the scope of the invention or the claims.

Conventional methods for obtaining biological samples from a subject are invasive, uncomfortable, and painful. For example, conventional glucose biosensors require that diabetics obtain blood samples by puncturing or lacerating their skin using a sharp blade or pin. The blood sample may then collected and delivered to a biosensor which detects glucose levels of the sample blood. While such biosensors are often marketed as being “pain-free,” users often experience some degree of discomfort that they may become inured to over repeated samplings. Regardless, conventional biosensors may cause discomfort, pain and may increase the chances of infection or bleeding.

Another disadvantage of the conventional biosensors is that they require several steps before they can analyze a biological sample. Conventional biosensors require breaching the skin, collecting the biological samples (e.g., blood), and delivering the obtained samples from the site of collection to the analyzing device. This multi-step process is time consuming and may cause contamination or loss of the biological sample during the collection and/or delivery. Additionally, if the sharp instruments that are used to breach the epithelium are not disposed of properly, cross-contamination of diseases, such as hepatitis, may result when other persons come in contact with the contaminated sharp instrument. A further disadvantage of the current biosensors is that they require relatively large sample volumes to provide accurate results.

Thus, various embodiment methods and apparatus are disclosed which provide for a safe and non-invasive transdermal sampling, and analysis of biological samples. The various embodiment methods and apparatus obtain and analyze transdermally extracted biological samples with minimal injury or sensation. In addition, the various embodiments obtain biological samples and deliver the samples to a biological sensor in a single step. Thus, potential risk of contamination may be minimized. In an embodiment, a voltage (or current) may be applied to a disruptor unit creating a localized heat that may be applied to the epithelium (i.e., skin) of a subject. The applied localized heat has been found to alter the permeability of the cells at a disruption site in the stratum corneum layer of the epithelium such that channels for fluid flow are created.

Interstitial fluid may permeate from these capillary-like channels and may be collected. The collected fluids may be tested for an analyte, such as glucose, by reacting the collected fluids to a biologically reactive element, such as an enzyme. The products of the biochemical reaction between the biological sample and the biologically reactive element may be analyzed electrochemically to deduce the concentration of the reactant from either a potential or an electrical current. The amount of potential or current that is detected may be mapped to determine levels of analytes or characteristics of the biological sample. Once the disruptor unit is removed from the skin, stratum corneum cells become impermeable again by returning to their original formation and closing the capillary-like channels.

The various embodiment methods and apparatus further allow for accurate real-time analysis of very small amounts of biological samples. In an embodiment, minute quantities of the interstitial fluid collected from the capillary-like channels of the stratum corneum may be used to determine various analyte levels.

The various embodiment methods and apparatus further enable the entire process of analyzing a biological sample including disrupting the skin cells, collecting biological samples, reacting the biological sample with a biologically reactive element, and sensing the signals generated by the reaction in singular device. By incorporating a sampling device and analyzing device in a singular package, a smaller biological sample may be required and the potential for contamination of the biological sample may be dramatically reduced. The time required to obtain a sample and perform an analysis of the sample may be also reduced.

Transdermal extraction of biological samples may require accessing body fluid that may be located under an intact skin surface. The skin is a soft outer covering of an animal, in particular a vertebrate. In mammals, the skin is the largest organ of the integumentary system made up of multiple layers of ectodermal tissue, and guards the underlying muscles, bones, ligaments and internal organs. Skin performs the following functions: protection, sensation, heat regulation, control of evaporation, storage and synthesis, absorption and water resistance.

Mammalian skin is composed of three primary layers: the epidermis, which provides waterproofing and serves as a barrier to infection; the dermis, which serves as a location for the appendages of skin; and the hypodermis (subcutaneous adipose layer).

Epidermis is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface and is made up of stratified squamous epithelium with an underlying basal lamina. Epidermis is divided into several layers where cells are formed through mitosis at the innermost layers. They move up the strata changing shape and composition as they differentiate and become filled with keratin. They eventually reach the top layer called stratum corneum and are sloughed off, or desquamated. The thickness of the epidermis is about 0.5 to 1.5 mm.

As illustrated inFIG. 1, epidermis is divided into the following five sub-layers or strata:Stratum corneum102 which consists of 25 to 30 layers of dead cells and has a thickness between 10 μm and 50 μm; Stratum lucidum103, Stratum granulosum104, Stratum spinosum105, and Stratum germinativum106 (also called “stratum basale”).

The apparatus of the various embodiments may be placed in direct contact with theskin100 and held in position by pressure or an adhesive. A precisely determined and controlled series of electrical pulses may be applied to one or more disruptor units disposed in or on the apparatus in order to produce localized heat and electrical fields that disrupt the cells of thestratum corneum layer102 of theskin100 without damaging the skin cells. The application of the precision controlled heat alters the permeability characteristic of the stratum corneum and produces capillary-like channels in the skin which allow interstitial fluid to flow out of the subject's body. The interstitial fluid may be collected and directed across the surface of the apparatus. On the surface of the apparatus, the interstitial fluid may come into contact with a sensor to determine composition or presence of a certain analyte(s). One such sensor may utilize a biologically reactive element, such as an enzyme. One or more pairs of electrochemical electrodes may be positioned in a manner to measure one or more biochemical analyte or physic-chemical properties of the interstitial fluid sample after the interstitial fluid reacts with the biologically reactive element. For sake of discussion, the dramatic increase in the permeability of the stratum corneum due to the localized application of heat may be referred to as a disruption process. The element which produces the localized heat may be referred to as adisruptor202. During the disruption process the skin cells remain intact.

FIG. 2 illustrates the functional components of a transdermal sampling andanalysis device200 according to an embodiment. A transdermal sampling andanalysis device200 may include adisruptor202 connected to the positive and negative electrical poles of asignal generator204a,204b. In an embodiment, thedisruptor202 may function as a resistive element. After a brief period of increased permeability due to the application of localized heat, the cells return to their normal function. In an embodiment, adisruptor202 produces heat as electrical current is passed through it. When placed on the skin, the localized heat generated by the disruptor element may cause disruption to the skin cells facilitating the flow of interstitial fluid onto the surface of the transdermal sampling andanalysis device200. Thedisruptor202 may be made from a variety of materials which exhibit the appropriate heating and control properties to provide the precise heating control properties required to disrupt the skin cells without damaging them. In addition, the materials used to create thedisruptor202 may be selected for relative ease of manufacture as well as cost considerations. Materials such as titanium, tungsten, stainless steel, platinum and gold may be preferably used to form thedisruptor202. In a preferred embodiment, gold may be used to form thedisruptor202.

A transdermal sampling andanalysis device200 may further include a sensing element comprised ofcounter electrode208 and workingelectrode210. Theelectrodes208,210 may be coated with a biologically reactive element and coupled to electricallyconductive paths206a,206b. In an embodiment, the counter and workingelectrodes208,210 form anode and cathode of an electrolytic cell. Thecounter electrode208 may be coated with a biologically reactive element to facilitate the conversion of signals generated by a chemical reaction between the biological sample and the biologically reactive element to electrical signals.

Many different analysis techniques may be incorporated into the transdermal sampling and analysis unit to determine the levels and concentrations of various analytes in a biological sample. For example, amperometric, coulometric, potentiometric techniques may be each alternative techniques which may be incorporated into the transdermal sampling and analysis device to determine levels or concentrations of analytes in a biological sample. In addition, electrochemical impedance analysis techniques may be incorporated to detect the presence of particular antibodies in a biological sample.

As an illustration, amperometric techniques may be employed to detect the level or concentration of glucose in a fluid sample. Two electrodes may be separated and insulated from each other and have a voltage potential applied across the electrodes. Because the electrodes are physically decoupled, no current flows from one electrode to the other. The electrodes may be treated with a reactive agent which in the presence of a particular analyte produces ions through a chemical reaction. The produced ions facilitate the flow of electrical current between the electrodes as the biological sample containing the analyte may be allowed to flow over the surface of the both electrodes. The relative number of ions produced in the reaction may determine the relative ease in which electrical current may flow. In other words, as a higher concentration of the detected analyte is present in the biological sample, the relative current flowing between the electrodes will increase. Thus, the relative concentration of a particular analyte may be calculated based upon the magnitude of current or voltage drop detected between the two electrodes.

Similarly, coulometric methods use analytical chemistry techniques to determine the amount of matter transformed during an electrolysis reaction by measuring the amount of electricity (in coulombs) conducted or produced. Transdermal sampling and analysis devices incorporating potentiometic methods measure potential under the conditions of no or low current flow. The measured voltage potential may then be used to determine the analytical quantity of the analyte of interest. Transdermal sampling and analysis devices incorporating electrochemical impedance method measure the dielectric properties of a medium as a function of frequency.

In an exemplary embodiment, when analyzing concentrations of glucose in a biological sample, enzymatic conversion of glucose to gluconolactone may yield electrons which may be captured to generate anodic current between the sensingelectrodes208,210, also referred to ascounter electrode208 and workingelectrode210. Electricalimpedance sensing electrodes208,210 may be configured to determine an electrical impedance spectroscopy across thesensing electrodes208,210. The magnitude of the electrical current generated as a result of the chemical reaction may be proportional to the amount or concentration of glucose contained in the obtained biological sample. In an embodiment, a voltage potential may be applied to the counter and workingelectrodes208,210 using a power generator (not shown). Once the biological sample reacts with the reactive biological element coating theelectrodes208,210, the ions that may be released from the conversion of glucose to gluconolactone facilitate generation of a current across the working and counter electrodes. In such a scenario, the working electrode may function as an anode and the counter electrode may function as a cathode or vice versa. The level of the current may depend on the amount of glucose that is in the biological sample and is converted to gluconolactone. The current that may be generated may be measured by an ammeter, the measurement of which may directly correlate to the level of glucose in the collected biological sample.

The counter and workingelectrodes208,210 may be made from any of a variety of materials which exhibit satisfactory conductivity characteristics and appropriate to the specific measurement used. In addition, the materials used to create the electrodes may be selected for relative ease of manufacture as well as cost considerations. Examples of materials exhibiting satisfactory conductivity characteristics for use as the counter and workingelectrodes208,210 may include platinum, silver, gold, carbon or other materials.

A transdermal sampling andanalysis device200 may further include areservoir212 for collecting and containing biological samples such as interstitial fluids that flow from capillary-like channels in disrupted stratum corneum. As interstitial fluid may be released and begins to flow over the transdermal sampling andanalysis device200, thereservoir212 provides a volume for the interstitial fluid to collect within. By collecting within thereservoir212, the interstitial fluid may be contained while the analysis of the sample by the sensing electrodes proceeds. Thereservoir212 may be formed under thedisruptor202 andsensing electrodes208,210. When the transdermal sampling andanalysis device200 is place on the subject's skin with thedisruptor202 contacting the skin, the reservoir may effectively be positioned above thedisruptor202 andelectrodes208,210 to contain the released fluid sample. Thereservoir212 may include a cover or lid to more effectively contain the fluid. A cover or lid is discussed in more detail below with respect toFIGS. 13A and 13B. Areservoir212 may be created using conventional methods known in the art. For example, areservoir212 may be created by the buildup of material such as ceramic orpolymer211 on the first side of a supporting base (e.g., substrate214) in the non-reservoir area either by additive process or by a subtractive process such as photolithography. Alternatively, a spacer material, discussed in more detail below, may be disposed between the lid andsubstrate214 to create a cavity for fluid to collect.

Asubstrate214 may form the support on which other transdermal sampling andanalysis device200 components may be positioned or attached. The substrate may be formed of a flexible material such that the substrate and components built thereon may deform to conform with the contours of the user's skin. Alternatively, the substrate may be formed of a rigid material such that the user's skin may be forced to deform to conform with the shape of the substrate. Thesubstrate214 may include a first or top side and a second or back side. The transdermal sampling and analysis components may be attached to the first side of thesubstrate214. Thesubstrate214 may include certain characteristics to accommodate all the functions of the transdermal sampling andanalysis devices200 of the various embodiments. For example, asubstrate214 may have to withstand various etching and or photo-lithography processes which deposit materials to form thedisruptor202 andelectrodes208,210 without being damaged. In addition, the first side of thesubstrate214 may undergo an etching process to create thereservoir212. In addition, it may be desirable for thesubstrate214 to exhibit certain thermal conductivity properties. For example, it may be desirable for the heat generated by thedisruptor unit202 to remain localized and concentrated. Accordingly it may be desirable for the substrate to have a high thermal resistivity such that heat generated by the disruptor is not conducted by thesubstrate214 to areas other than those directly in contact with thedisruptor unit202. Additionally, it may be desirable for the substrate to possess a resistance to thermal expansion.

Different substrates214 may be used as a base in a transdermal sampling andanalysis device200.Substrates214 with high coefficient of thermal expansion may flex or buckle as voltage (or current) is applied to thedisruptor202 and heat is generated. The flexing or buckling action may displace thedisruptor unit202 away from the surface of theskin100, resulting in an insufficient heating of the stratum corneum. Consequently, the permeability of the stratum corneum may not be altered sufficiently to allow for the flow of interstitial fluid. The end result being that the volume of the obtained biological sample is not sufficient to adequately analyze. Thedisruptor202 may be required to continuously contact theskin100 to create the capillary-like channels in the stratum corneum which may allow interstitial fluid to flow from the body of the subject onto the transdermal sampling andanalysis device200. Thus, a lowthermal modulus substrate214 may be selected that does not displace the disruptor202 from theskin100.

Further, repeated heating and cooling of thesubstrate214 may damage components of the transdermal sampling andanalysis device200 that may be attached to thesubstrate214. For example, differences in thermal expansion characteristics between the materials used for thedisruptor202 and thesubstrate214 may result in separation of the disruptor202 from thesubstrate214. In other words, the disruptor may begin to peel away from the substrate after repeated heating and cooling cycles. Accordingly, in a preferred embodiment the substrate may exhibit high thermal resistivity (low thermal conductivity) properties while mirroring the low thermal expansion characteristics of thedisruptor202 material.Different substrates214 may have different thermal expansion properties. For example,most metals substrates214 have coefficient of thermal expansion of about 5˜10 ppm/° C.; glass has a coefficient of thermal expansion of ˜8 ppm/deg F.; common plastics have coefficient of thermal expansion of 20˜30 ppm/° C.

However, in some alternative embodiments, the thermal expansion characteristics of the materials used in both thesubstrate214 may be manipulated to advantageously result in a mechanical movement of the substrate. This mechanical movement of thesubstrate214 may cause a break, disruption, or dislocation of bonds in the lipid barrier membrane, further enabling or assisting in the displacement of biological fluid out from the interstitial region, over and through the transdermal sampling ananalysis device200. For example, as electrical current is applied through thedisruptor202 heat may be generated. The heating of thedisruptor202 causes thesubstrate214 housing thedisruptor202 to also heat. This heating results in an expansion of thesubstrate214 material in accordance with coefficient of thermal expansion. As the current applied to thedisruptor202 is disengaged, both thedisruptor202 and the surroundingsubstrate214 will cool. This cooling results in a contraction of thesubstrate214 material. As discussed in more detail below, current to thedisruptor202 may be pulsed. The pulsing on and off of the applied current may cause in a rhythmic expansion and contraction cycle of thesubstrate214 to result in a mechanical movement of the substrate, perpendicular to its plane to enhance flow of biological fluid out of the interstitial region. Materials having a sufficient coefficient of thermal expansion may result in a translation of thesubstrate214, perpendicular to its plane, of between 0.05 μm and 3.0 μm. In a preferred embodiment, materials having a coefficient of thermal expansion are selected to result in a translation of thesubstrate214, perpendicular to its plane, of between 0.1 μm and 0.6 μm.

In an embodiment, thesubstrates214 may include physical and/or chemical properties to accommodate certain temperatures without being damaged or cause damage to the components of the transdermal sampling andanalysis device200. In an embodiment, adisruptor202 generating temperatures as high as 200° C. may be attached to thesubstrate214. Thus, thesubstrate214 may have to withstand such high temperatures without melting, permanently deforming or conducting the heat to other components of the transdermal sampling andanalysis device200.

Even if asubstrate214 does not melt or permanently deform under high temperatures, thesubstrate214 may expand or contract due to varying temperatures. Because components of the transdermal sampling andanalysis device200 may be fixedly attached to thesubstrate214, expansion and contraction of thesubstrate214 may cause the attached components to detach and cause damage to the configuration of the transdermal sampling andanalysis device200.

To reduce or eliminate the size variation of thesubstrate214 under varying temperatures,different substrates214 may be considered. In an embodiment, asubstrate214 made of a material with a coefficient of thermal expansion of about 10 to 20 ppm/deg F. may be used to reduce the expansion/contraction effects of thesubstrate214 when exposed to high heats of about 100° C. to 200° C. In a further embodiment, asubstrate214 made of a material with a coefficient of thermal expansion of about 10 to 12 ppm/deg F. may be used. In a further embodiment, asubstrate214 may have a coefficient of thermal expansion that may be within a 20% deviation from the CTE of thedisruptor202 material.

To reduce or eliminate conduction of heat from thedisruptor202 attached to thesubstrate214 to other components of the transdermal sampling andanalysis device200, alternative materials may be considered for thesubstrate214. In an embodiment, thesubstrate214 may be formed from a material having a coefficient of thermal conductivity of about 0.1 to 1.1 W/m*K to reduce the conduction of heat from thedisruptor202 to other components of the transdermal sampling andanalysis device200 or to other unintended areas of the skin of the subject beyond the portion directly in contact with thedisruptor202. In a further embodiment, thesubstrate214 may be made from a material having a coefficient of thermal conductivity of about 0.1 to 0.2 W/m*K. In a further embodiment, asubstrate214 may be made from a material having a coefficient of thermal conductivity of about 0.13 W/m*K or lower.

In an embodiment, selection of asubstrate214 for the transdermal sampling andanalysis device200 may depend on the coefficient of thermal expansion and conductivity of the material used to make thedisruptor202 of the transdermal sampling andanalysis device200. For example, thesubstrate214 may be made of a material which has a coefficient of thermal expansion that deviates from the CTE of the material used in thedisruptor202 by less than 50%, and preferably by less than 20%. In a further embodiment, thesubstrate214 may be made of a material which has a coefficient of thermal conductivity (CTC) that is lower than 0.5 W/(m·K)

In an embodiment, thesubstrate214 suitable for use in the transdermal sampling andanalysis device200 of the various embodiments may be made of a variety of materials such as glass, plastic, metal or silicon.

In an embodiment, thesubstrate214 may be made of plastic. When heat is applied to plastics, the plastic material typically shrinks in size before expanding in size. Because of this unique characteristic of plastic, application of heat to asubstrate214 made of plastic may cause damage to the components of the transdermal sampling andanalysis device200 attached to theplastic substrate214. To prevent the initial contractions, the plastic material used to make thesubstrate214 may be annealed plastics (i.e., plastics which have been previously heated to remove or prevent the internal stress caused by the initial shrinkage). Annealed plastics are known in the art and may be produced by annealing a plastic material to cause a change in its properties.

In a further exemplary embodiment, thesubstrate214 may be made of a polyimide such as Kapton™. Kapton™ is a polyimide film developed by DuPont™ which can remain stable in a wide range of temperatures, from −273 to +400° C. (0-673 K).

A biologically reactive element, such as an enzyme, may be applied to the first side of the substrate. For example, the biologically reactive element may be applied to the workingelectrode210, thecounter electrode208 or both. As the stratum corneum is disrupted and interstitial fluid begins to flow through the stratum corneum into thereservoir212 by capillary action of the structure. The interstitial fluid may be directed to flow into thereservoir212 and specifically over the surface of the counter and workingelectrodes208,210. The obtained fluid may come into contact with the biologically reactive element on the surface of the counter and workingelectrodes208,210 causing a chemical reaction that releases energy in the form of electrons. The counter and workingelectrodes208,210 may form anode and cathode of an electrolytic cell, enabling current flow through a device which can measure the current at a controllable potential. Thus, the electrons (ions) released from the chemical reaction between the biological sample and biologically reactive element may be converted into electrical signals. The electrical signals generated by the chemical reaction may be measured to determine the amount of a target analyte in the obtained biological sample.

Excessive thickness of the biologically reactive elements on the first side of the substrate may cause certain problems during the manufacturing process or during the operation of the device. For example, greater thickness of the biologically active layer requires greater depth of channels to allow space for the biological sample to flow over the electrodes. If the applied biologically reactive element layer is too thick, greater than 10 micrometers for example, such as common in commercial glucose transdermal sampling and analysis devices, it may clog or fill thechannels222 that may be configured to guide the biological sample over the electrodes rendering the transdermal sampling andanalysis device200 dysfunctional, or causing the need for increased channel thickness at increased cost.Channels222 are discussed in more detail below. In an exemplary embodiment, to avoid clogging thechannels222 and blocking the movement of the biological sample over the electrodes, the biologically reactive element may be applied in such a way as to result in a thickness of less than 5 micrometers, and preferably less than 1 micrometer. This can be accomplished by the use of a system such as described by Eugenii Katz, biochemistry and bioenergetics-42 (1997) 95-104 or other known method of thin sensor layer deposition. By reducing the thickness of the biologically reactive element, potential clogs to thechannels222 in the transdermal sampling andanalysis device200 may be prevented without the additional cost of increased channel depth.

One example of a commonly used biologically reactive element may be the enzyme Glucose Oxidase (GOD). Another example of a commonly used biologically reactive element may be the enzyme glucose dehydrogenase. In an exemplary embodiment, GOD may be applied to cover the surface of the workingelectrode210. To determine a subject's glucose levels, a transdermal sampling andanalysis device200 with adisruptor202 may be applied in direct contact with the skin cells. By applying a voltage (or current) across the terminals of thedisruptor202, a precision controlled heat may be produced and localized to thedisruptor202 site. The localized heat may be applied against the skin to alter the permeability of the skin cells and consequently creates capillary-like channels. Interstitial fluid may flow out of the capillary-like channels into thereservoir212 and over the counter and workingelectrodes208,210. The glucose molecules in the interstitial fluid may react with GOD covering the surfaces of the workingelectrode210. Glucose oxidase catalyzes a breakdown of glucose in the interstitial fluid to gluconolactone, releasing electrons to a mediator such as K₃Fe[CN]₆. The electron mediator (or electron shuttle) may transfer electrons to the workingelectrode210, where anodic potential has been applied such that the mediator may be oxidized. The oxidized mediator may be then able to accept another electron from the glucose conversion reaction to repeat the process. The electrons released in this oxidation reaction may travel through the workingelectrode210 towards the counter electrode,208 generating a current. The magnitude of the sensed electrical current generated by this reaction may be proportionally related to the concentration levels of glucose in the interstitial fluid. Thus, by determining the magnitude of current generated across the working and counter electrode, one may determine the relative amount of glucose in the obtained sample.

FIG. 3 illustrates a top view of a transdermal sampling andanalysis device200 showing an embodiment orientation and configuration of the functional components of the transdermal sampling andanalysis device200. The transdermal sampling andanalysis device200 may include adisruptor202 connected to two electricalconductive paths204a,204b. Theconductive paths204a,204bmay be coupled to the positive and negative nodes of a power source (not shown). Thedisruptor202 may be placed adjacent to a workingelectrode210 andcounter electrode208. The counter and workingelectrodes208,210 may be connected to electricalconductive paths206a,206b, respectively.

The surface of the counter and workingelectrodes208,210 may be patterned withsupport structures220 which displace theelectrodes208,210 from the surrounding skin of the subject. As the transdermal sampling andanalysis device200 may be pressed against the subject skin, it may be necessary to displace theelectrodes208,210 from the surrounding skin in order to allow the free flow of obtained interstitial fluid over the surface of theelectrodes208,210. The surroundingskin100 may deform across the surface of theelectrodes208,210, effectively preventing the biological sample from coming into contact with the electrode surfaces. By placingsupport structures220 over the electrodes, the surrounding skin may be effectively lifted off the surface of the electrode. The various patterns ofsupport structure220 may also createchannels222 which direct the biological samples over the entire surface working andcounter electrodes208,210 due to capillary action. These patterns may be of any shape or arrangement. For example, the counter and workingelectrodes208,210 may be configured to include star shaped channel supports220 to manipulate the movement of biological sample over the entire surface of the counter and workingelectrodes208,210.

Because the amount of biological sample required is minute and the surface area of the counter and workingelectrodes208,210 may be relatively small, a uniform coverage of the counter and workingelectrodes208,210 by the biological sample may enhance the accuracy of the final analysis of analytes. Results obtained from a transdermal sampling andanalysis device200 in which the entire surface of a counter and workingelectrodes208,210 are covered require less time and volume of biological sample for analysis and may be more accurate.

FIG. 4 illustrates a top view of another embodiment transdermal sampling andanalysis device200. The functional elements of the transdermal sampling andanalysis device200 may be disposed upon the surface of asubstrate214 and may be configured to include counter and workingelectrodes208,210 that may be inter-digitated. In such a configuration, more than one counter and workingelectrodes208,210 may be used to create the inter-digitated configuration. For example, a total of three electrodes may be used to create the inter-digitations; twocounter electrodes208aand208bas well as one workingelectrode210. The counter and workingelectrodes208,210 may be coupled to a current or sensing unit via electricallyconductive paths206a,206b.Elongated channels222 may be formed using long channel supports220. Thechannels222 may cover the entire surface of the counter and workingelectrodes208a,208b,210. Adisruptor202 configured in a serpentine shape may be positioned adjacent to the counter and workingelectrodes208a,208b,210. Areservoir212 may be created to surround thedisruptor202 and the counter and workingelectrodes208a,208b,210. Thedisruptor202 may be connected to the positive and negative electrical poles of asignal generator204a,204b.

A biological sample, such as interstitial fluid, may flow from capillary-like channels created by thedisruptor202 into thereservoir212 through capillary action. As the biological sample flows into thereservoir212, thechannels222 and channel supports220 may assist the movement and direction of the biological samples in thereservoir212 to disperse the biological sample over the entire surface of the counter and workingelectrodes208a,208b,210 through further capillary action caused by the relative hydrophilic properties of the selectedchannel support220 material, as described in more detail below.

Exhaust ports or vents224 may be present on the side of thereservoir212 towards which the biological sample may move. The exhaust ports/vents224 may relieve any air pressure that would otherwise be caused by air trapped within thereservoir212 and prevent the biological sample from moving towards the far side of thereservoir212. In the embodiment shown inFIG. 4, thereservoir212 may be in a shape of a trapezoid to allow biological samples to flow from thedisruptor202 over the working andcounter electrodes208,210 using thechannels222 and the channel supports220. In alternative embodiments, theexhaust port224 may be configured to direct the vented gases back toward thedisruptor202 so that the gases may be recirculated back through a hole in a lid1302 (seeFIG. 13B and discussion below regarding lid). Embodiments utilizingexhaust ports224 may be referred to as vented embodiments, whereas embodiments that do not utilize exhaust ports may be referred to as unvented or non-vented embodiments.

FIGS. 5A-5D illustrate top views of various embodiment transdermal sampling and analysis devices421-424 each having a different configuration of the functional components. The embodiments shown in each ofFIGS. 5A-5D possess different disruptor202(5A)-202(5D) configurations, but assume for purposes of this discussion that disruptors202(5A)-202(5D) may be formed of the same material. Moreover, for purposes of this discussion it may be assumed that the same voltage (or current) may be applied across each of disruptors202(5A)-202(5D).

Similar to the transdermal sampling and analysis device shown inFIG. 4,FIG. 5A illustrates a transdermal sampling andanalysis device421 including interdigitated counter and workingelectrodes208a,208b,210 and a disruptor202(5A) with a serpentine configuration. In the embodiment shown inFIG. 5A the cross section of disruptor202(5A) has a relatively small wire gauge (i.e., larger cross section diameter). The smaller gauge may result in a disruptor202(5A) having a relative lower resistive value and thus a lower localized heat as compared to adisruptor202 having a higher resistive value where the same voltage may be applied.

FIG. 5B illustrates a top view of another embodiment transdermal sampling andanalysis device422. The functional components of the embodiment shown inFIG. 5B are similar to those shown inFIG. 5A. In particular, the total length of the disruptor202(5B) shown inFIG. 5B may be the same disruptor202(5A) shown inFIG. 5A. In addition, the total area covered by the disruptor202(5B) shown inFIG. 5B may be the same as disruptor202(5A) shown inFIG. 5A. However, the gauge of the serpentine coils of disruptor202(5B) shown inFIG. 5B may be shown to be larger (i.e., smaller cross sectional dimension) than the disruptor202(5A) shown inFIG. 5A. Consequently, when the same voltage (or current) applied to the disruptor202(5A) inFIG. 5A may be applied to the disruptor202(5B) inFIG. 5B, a higher temperature localized heat may be generated due to the increased resistive value. Since the higher temperature produced by the disruptor202(5B) shown inFIG. 5B may be distributed over the same relative area as that produced by the disruptor202(5A) shown inFIG. 5A, the power density of the disruptor202(5B) shown in the embodiment ofFIG. 5B may be much higher relative to the disruptor202(5A) shown inFIG. 5A.

FIG. 5C illustrates a top view of another embodiment transdermal sampling andanalysis device423. In contrast to disruptor202(5A) shown inFIG. 5A, disruptor202(5C) shown inFIG. 5C has a larger gauge than disruptor202(5A), but has fewer windings and covers a smaller total area than disruptors202(5A) and/or202(5B). As compared to disruptor202(5A), because disruptor202(5C) has a smaller gauge than disruptor202(5A), disruptor202(5C) will typically have a higher resistive value than disruptor202(5A). However, because disruptor202(5C) also has fewer windings than disruptor202(5A), the total length of disruptor202(5C) may be shorter than disruptor202(5A). As a result, the increase in resistive value of disruptor202(5C) over disruptor202(5A) due to the larger gauge may be effectively negated and the resistive value of disruptor202(5C) may be the same as disruptor202(5A). However, because disruptor202(5C) covers a significantly smaller total area as compared to disruptor202(5A), the power density of disruptor202(5C) may be significantly greater relative to that of disruptor202(5A). As compared to disruptor202(5B), disruptor202(5C) has the same gauge value as disruptor202(5B) but has fewer windings. As a result, the total length of disruptor202(5C) may be less than disruptor202(5B). Consequently, disruptor202(5C) will have a lower resistive value relative to that of disruptor202(5B). However, since disruptor202(5C) covers a significantly smaller total area as compared to disruptor202(5B), the power density of disruptor202(5C) may effectively be the same relative to that of disruptor202(5B).

FIG. 5D illustrates an embodiment transdermal sampling andanalysis device424 including counter and workingelectrodes208,210 with large smooth surfaces. In contrast to the configurations shown inFIGS. 5A-5C, thereservoir212 and the disruptor202(5D) may be rectangular in shape as opposed to serpentine. In addition, theelectrodes208,210 may be shown as rectangular electrodes that are not interdigitated. The relative resistive value of disruptor202(5D) may be much lower than that of disruptors202(5A)-202(5C) as its gauge may be nearly that of disruptor202(5A) but total length may be nearly that of202(5C). In addition, because disruptor202(5D) covers approximately the same total area as disruptor202(5C), the power density of disruptor202(5D) may be less relative to that of disruptor202(5A), disruptor202(5B) and disruptor202(5C). The various embodiments may be designed to deliver heat to the subject's skin with a power density of 1-10 W per mm². In a preferred embodiment the disruptor delivers heat to the subject's skin with a power density of 2-5 W per mm².

As shown inFIGS. 5A-5D, the transdermal sampling and analysis devices421-424 of the various embodiments may be made using a variety of different disruptor202(5A)-202(5D) configurations. As discussed above, the size and shape of the disruptor may affect its resistive characteristics and consequently, its ability to generate a localized heat. In addition, the material selected to form the disruptor may also affect its resistive characteristics and consequently, its ability to generate a localized heat. As with electrode material selection, disruptor materials may be selected from a wide variety of materials exhibiting satisfactory electrical conductance/resistive properties such that sufficient heat may be generated when specific voltages are applied to the disruptor leads. In addition, thermal conduction and resistance characteristics should be observed in an optimal disruptor material. Finally, ease of manufacturing processing and cost may determine the final selection of disruptor material. For example, adisruptor202 may be made of nichrome, titanium, tungsten, or gold. In a preferred embodiment, thedisruptor202 may be made from gold.

As discussed above with reference toFIGS. 5A-5D, thedisruptor202 may be formed in a variety of configurations.FIGS. 6A-6E illustrate additional shapes that thedisruptor202 may be formed. For example, adisruptor202 may be formed in serpentine, circular, crescent, semi-circular, linear, square, rectangular, trapezoidal, hexagonal and triangular shapes. Each unique shape may impact the manner in which the generated heat may be localized. Studies have shown that that the resulting sensation experienced by the subject induced by the varying disruptor shape also varies. By varying the shape of thedisruptor202, the sensation or discomfort experienced by the subject may be increased or decreased.

FIG. 6A illustrates a top view of anembodiment disruptor202 with a linear shape.FIG. 6B illustrates a top view of anembodiment disruptor202 formed in the shape of the Greek letter omega.FIG. 6C illustrates a top view of anembodiment disruptor202 formed in a serpentine shape.FIG. 6D illustrates a top view of anembodiment disruptor202 formed in a rectangular shape. Disruptor shape configuration may affect the relative sensation or discomfort experienced by the subject from which the biological sample may be drawn. In a preferred embodiment, the disruptor unit may be formed such that the perimeter of the disruptor preferably forms a rectangle. Such preferred disruptor units may be formed fromsolid disruptors202 such as that shown inFIG. 6D or in alternative serpentine configurations such as shown inFIG. 6C. The serpentine configuration has some advantages. For example, because the serpentine disruptor may be formed by a long, thin coil (as compared to a solid rectangle), the resistive characteristic of the disruptor may be much larger (assuming similar or same material). In addition, the thinner cross section of each coil also contributes to a higher overall resistive value of the disruptor unit. In this manner, the serpentine shaped disruptor may occupy a generally rectangular area, while providing sufficiently high resistance to produce the required localized heating levels to obtain a transdermal biological sample with minimal sensation and discomfort to the subject.

In an embodiment, the area determined by the perimeter surrounding adisruptor202 may affect the amount of biological sample that may be collected or the amount of sensation or sensation that may be experienced by the subject. In addition to absolute area, the aspect ratio of thedisruptor202 may impact sensation versus fluid generation level. Aspect ratio is a ratio of the area of theskin100 that adisruptor202 may cover as compared to the parameters of thedisruptor202, such as the disruptor's length and cross-sectional area. Different aspect ratios may affect the process of disruption of the skin cells and levels of sensation differently. For example, if the skin area that thedisruptor202 may cover is of excessive aspect ratio (e.g., a long and thin disruptor such as shown inFIG. 6A), the use of thedisruptor202 may cause high levels of sensation without obtaining a sufficient amount of biological sample. A preferred aspect ratio has been found to be about 2:1. A more preferred aspect ratio may be 1:1 (i.e., a square or circular)+/−50%. At such preferred aspect ratios, subjects have exhibited the least sensation or discomfort while obtaining a sufficient amount of biological sample.

In an embodiment, where the aspect ratio may be about 2:1, thedisruptor202 may cover a rectangular area with a length of about 150 μm-400 μm and width of 50 μm-200 μm. In a further embodiment, thedisruptor202 may have a length of about 200 μm-400 μm and a width of 100 μm-200 μm.FIG. 7 illustrates an exemplaryserpentine disruptor202 with a length of 200 μm and a width of 100 μm. In a preferred embodiment, the dimensions of thedisruptor202 may include a length of 120 μm and width of 60 μm. By minimizing the size of the disruptor unit, the relative sensation and discomfort may be likewise minimized. However, limits on manufacturing processes as well as the need to disrupt a large enough area of stratum corneum to obtain a sufficiently large enough sample of biological material may dictate the minimal effective size of the disruptor unit. Thedisruptor202 with dimensions of 120 μm×60 μm may obtain a sufficient amount of biological sample while causing a negligible sensation or discomfort to the subject.

In a further embodiment, other aspect ratios less than 2:1 may also be used. For example, adisruptor202 may have a length of 100 μm and a width of 60 μm. In a further embodiment, where the aspect ratio may be about 1:1, thedisruptor202 may cover a square area with a length and width of about 50 μm-400 μm. In a further embodiment, thedisruptor202 may have a length and width of about 100 μm-400 μm. In an exemplary embodiment, aserpentine disruptor202 with a length and width of 200 μm may be used. In a preferred embodiment, the dimensions of thedisruptor202 may have a length and width of about 120 μm.

In a preferred embodiment, thedisruptor202 may have the dimensions of 200 μm×200 μm. In a more preferred embodiment adisruptor202 may have the dimensions of 60 μm×60 μm.

Electrical resistance of a disruptor may be calculated using the following equation:
R=ρL/A

where,

R is the electrical resistance of a uniform specimen of the material (measured in ohms, Ω)

ρ is electrical resistivity of the material (measured in ohm-meters, Ω-m)

L is the length of the piece of material (measured in meters, m); and

A is the cross-sectional area of the specimen (measured in square meters, m²).

By varying the value of each of these parameters, different electrical resistances may be achieved. For example, the thinner the cross-section of the specimen used in the disruptor, the greater the electrical resistance of the disruptor. Similarly, the longer the length of the material used in thedisruptor202, the greater the electrical resistance of the disruptor. Conversely, a wider cross section or shorter disruptor may result in a lower electrical resistance of the disruptor.

The higher the electrical resistance, the greater the heat generated given a constant current applied through thedisruptor202. Thus, to obtain a desired heat level, the material used in thedisruptor202 should achieve a desired electrical resistance. Because electrical resistivity of a material may be constant, the length and cross-sectional area of the material may be adjusted to achieve a desired electrical resistance which in turn may generate a desired heat level. For example, to achieve high electrical resistance in adisruptor202 which employs a short piece of gold material, the cross-section area of the gold material may be reduced. Likewise, to achieve high electrical resistance indisruptor202 which uses a gold material with a large cross-section area, the length of the gold material may be increased.

While the serpentine configuration of the disruptor creates multiple sites for heat production on the skin, the constructive interference of the heating generated effectively applies a singular source of heating to the subject skin.FIG. 8 illustrates a cross-sectional view of an embodimentserpentine disruptor202 positioned next to theskin100. For example, eachcoil802 may generate heat resulting from the resistance to electrical current applied to the leads of thedisruptor202. The generated heat may be conducted through the layers of the skin. The discrete heating from eachcoil802 may constructively interfere with the heating generated from other neighboringcoils802 to create auniform heat gradient804. A uniform,continuous heating gradient804 may cause uniform and effective disruption to the skin cells. In this manner, the serpentine configuration of the disruptor provides the same uniform heating as can be achieved through use of a solid rectangular configuration for the disruptor. Moreover, the serpentine configuration may provide a disruptor with greater electrical resistance as compared to a solid rectangular disruptor confined to the same area.

In aserpentine disruptor202, the distances of thecoils802 from one another may determine whetheruniform heating gradient804 may form as discrete heat sources as they travel through the stratum corneum. If the distances between thecoils802 are too large, a uniform andcontinuous heating gradient804 may not form at all or may form at a skin level below the stratum coneum, thus, failing to effectively and uniformly disrupt the cells of the stratum corneum. In an embodiment, thecoils802 of theserpentine disruptor202 may be about 5 μm to 40 μm apart. In a preferred embodiment, thecoils802—of theserpentine disruptor202 may be about 15 μm apart.

Given the variety of disruptor properties that may be varied (e.g., size, shape, gauge, material, current applied, etc.) a disruptor may be formed and implemented that exhibits the desired electrical characteristics to generate a sufficient fluid sample while imparting negligible sensation and/or discomfort to the patient. For example, assuming no other changes, as the size (area) of the disruptor increases so does the amount of fluid extracted. However, again assuming no other changes, as the size (area) of the disruptor increases so does the amount of sensation and discomfort experienced by the patient. Thus, certain proportional relationships may be known. The amount of sensation or discomfort a patient may experience may be proportionally related to the area of the disruptor, the aspect ratio of the disruptor, and the power density that applied. Likewise, the amount of fluid that can be extracted may be proportionally related to the area of the disruptor and the power density that applied. Tests have indicated that an applied power density of 1 W per mm²may be the minimum amount of power required to disrupt a patient's stratum corneum. In practice a disruptor may be constrained by a number of other factors. For example, in a portable application there may be voltage/current constraints resulting from the use of a particular battery, thus, dramatically impacting the power density requirements. Economic or manufacturing constraints may limit the materials from which the disruptor may be manufactured. When faced with any of these constraints, a disruptor may still be designed by varying the combination of disruptor properties so that each of the constraints are met.

As previously discussed, thedisruptor202 may essentially operate as a resistor which, when a voltage (or current) is applied to the leads of thedisruptor202 creates a localized heat source. The amount of heat required to disrupt the skin cells to obtain sufficient amounts of biological samples and cause the least discomfort or sensation may depend on different variables, such as the thickness of theskin100 and the concentration of nerve endings on theskin100. Furthermore, sensation and discomfort are subjective to each individual subject. However, the stratum corneum is generally about 50 μm in thickness. It may be thicker or thinner at various locations of the subject. For example, it is thicker at the palm of the hands and soles of the feet and thinner on the eyelids. In an embodiment, the heat generated by the disruptor may result in a heater temperature of about 100° C. to 200° C. The lower temperatures may cause less sensation while higher temperatures may produce larger amounts of biological sample. A desired location for applying the heat to disrupt the skin cells may be on the medial surfaces of the forearm. Given the relative thickness of the stratum corneum at this location as well as the relative number of nerve endings at this location, it may be preferable to apply at 50° C. to 150° C. from the disruptor to cause the disruption in the stratum corneum. In a more preferred embodiment, the temperature of the disruptor may be about 90° C. to 110° C.

In an embodiment, since different subjects may have different skin thickness levels, calibration of the transdermal sampling andanalysis device200 of the various embodiments may be required to generate sufficient heat for obtaining the most amounts of biological samples with the least amount of sensation. Thus, the level and duration of the temperature of thedisruptor202 may be adjusted for different subjects.

In an embodiment, the disruption of theskin100 may occur when heat of about 85° C. to 140° C. from thedisruptor202 may be applied to the skin surface for durations of about 100 ms to 200 ms. In a further embodiment, the disruption of the skin may occur when heat of 140° C. from thedisruptor202 may be supplied to theskin100 surface for durations of about 120 ms to 160 ms. In a preferred embodiment, the disruption of theskin100 may occur when heat of 140° C. from thedisruptor202 may be supplied to theskin100 surface for duration of about 140 ms.

In order to safely operate on and around the subject, lower voltages and currents may be desirable. Voltages of 10 V or higher may be detected by the body and have been observed in encephalograms. Thus, to reduce the effects of the voltage on the body, it may be preferable to use voltages lower than 10 V. Since there may be a limit on the amount of voltage that may be safely applied to a subject, the electrical resistance of thedisruptor202 may be adjusted based on the desired voltage. Likewise, there may be a limit on the amount of current that may be safely applied to a subject, the electrical resistance of thedisruptor202 may be adjusted based on the desired current. In an embodiment, the voltage supplied to thedisruptor202 may be about 1 V to 10 V. In a preferred embodiment, the voltage supplied to thedisruptor202 whose area is about 2×10⁻⁸m²may be about 2 V. In another embodiment where a current source applies a current, the current supplied to thedisruptor202 may be about 35 mA to 145 mA. In a preferred embodiment, the current supplied to thedisruptor202 may be about 100 mA. For this preferred embodiment, the corresponding power density per unit area of the disruptor on the skin may be about 5×10⁶W/m², the energy per pulse may be about 65 mJ, and the energy per unit area of the disrupter on the skin may be about 3×10⁶J/m²Since the amount of heat generated by a resistive element is dependent upon the resistive value of the resistive element and the amount of voltage (or current) applied across (through) the resistive element, thedisruptor202 suitable for use in the various embodiments may include an electrical resistance of about 5 Ohm to 100 Ohm. In a preferred embodiment, the electrical resistance may be about 15 Ohm to 50 Ohm. In a preferred embodiment, the disruptor may have an electrical resistance of about 22 Ohm. One of skill in the art would recognize that voltage and current may be proportionally related to one another by Ohm's law. Much of the discussion herein may discuss the application of voltages to thedisruptor202. One of skill in the art would recognize that analogous current source limitations may apply.

To generate the desired heat at thedisruptor202, electrical current may be applied to theconductive paths204a,204bhaving a duty cycle that may vary from 0 to 100percent. The electrical current applied to adisruptor202 may be a direct or alternate current. A duty cycle is the fraction of time that the electrical current is being applied to thedisruptor202 and may be static (100%) or pulsed (<100%). It has been found that by pulsing the electrical current effective heating of the stratum corneum may be achieved while mitigating any sensation or discomfort experienced by the subject. In a preferred embodiment, a pulsed direct current may be applied to thedisruptor202. The pulsed direct current may be applied to theconductive paths204a,204bof adisruptor202 using a duty cycle of about 80 percent.

In an exemplary embodiment, current may be applied for a period of 200 ms. If the duty cycle is about 80 percent, the direct current may be turned on to apply electrical current to thedisruptor202 for about 160 ms and turned off for 40 ms during the 200 ms period.

In an embodiment, the frequency of a pulsed duty cycle may be about 1 Hz to about 1 kHz. In a preferred embodiment, the frequency of the pulsed duty cycle may be about 1 Hz to about 10 Hz. In a more preferred embodiment, the frequency of the pulsed duty cycle may be about 5 Hz.

For example, the frequency of the pulsed duty cycle may be 5 Hz for a duty cycle at 80 percent with a period of 200 ms. The pulsed duty cycle may have period of about 0.5 second to 5 seconds. In a preferred embodiment, the pulsed duty cycle may have a period of about 3 seconds to collect a sufficient amount of biological sample for testing. In a preferred embodiment, the voltage may be applied for a duration of 1 to 20 seconds.

In an exemplary embodiment, an electrical voltage of 2.2 V may be applied to thedisruptor202 with pulsed duty cycle of 80% for 3 seconds to generate temperature of 140° C. Ifdisruptor202 has the dimensions of about 100 μm×200 μm and electrical resistance of 22 Ohm, the power (P) over Area required to generate the required heat may be 5 W/mm²which may be calculated using the following equations:
P=I²R=V²/R=2.2V/22 Ohm=0.1 W
where,

R=V/I and where,

Power P is in Watts;

Voltage V is in volts; and

Resistance R is Ohms.

A=100 μm×200 μm=0.02 mm²

P/A=0.1 W/0.02 mm2=5 W/mm²

where,

is power; and

A is area of the disruptor.

The energy (E) per unit area required to generate 140° C. of heat in thedisruptor202 may be measured by the following equations:
E/A=Pt/A=1 J/mm²

where,

Energy is measured in Joules,

t is time at 0.2 s of one pulse; and

A is the area of disruptor.

The amount of biological sample required to be obtained by the transdermal sampling andanalysis device200 to accurately determine levels of an analyte may be about less than 40 nano-L. In a preferred embodiment, the amount of biological sample obtained by the transdermal sampling andanalysis device200 may be about less than 10 nano-L. In a more preferred embodiment, the amount of biological sample obtained by the transdermal sampling andanalysis device200 may be about 5 nano-L.

In an embodiment method, voltage may be applied to thedisruptor202 in a manner to reduce the amount of sensation felt by the subject. One method of reducing sensation may be to gradually and in a stepwise manner raise the level of the voltage applied to thedisruptor202 until it reaches a desired voltage. For example, if 1.8 V produces the most amount of fluid, to reduce sensation the voltage may be pulsed at different intervals before reaching 1.8 V. For instance, the voltage may be pulsed five times at 1.2 V, five times at 1.4 V, and five times at 1.6 V before applying 1.8 V to thedisruptor202. In this embodiment method, the pulses at lower voltages may cause some biological sample fluid to flow from theskin100. Even though this small amounts of the biological sample obtained at the lower voltages may not be enough to determine the levels of an analyte, the small amount of the biological sample may act as a thermal conductor to render thedisruptor202 more efficient and reduce the level of sensation felt by the subject at higher volts (i.e., 1.8 V). Thus, by increasing the voltage in a stepwise manner over a period of time, instead of applying the maximum voltage immediately, the same amount of biological samples may be obtained in the same amount of time while the amount of sensation may be reduced.

In addition, it may be noted that the application of electrical energy to thedisruptor202 may result in the formation of electrical fields surrounding thedisruptor202. The formed electrical fields may also alter the permeability characteristics of the stratum corneum. By increasing the localized electrical field formed by applying electrical energy to thedisruptor202, the permeability of the stratum corneum may also be increased. The increase in the permeability of the stratum corneum may require less heat imparted upon the stratum corneum to release a sufficient amount of biological fluid needed for an accurate analysis. Consequently, a lessening of the sensation or discomfort may be experienced by the subject.

FIG. 9 illustrates a top view of an embodiment transdermal sampling andanalysis device200 using more than onedisruptor202. To increase the amount of disruption to theskin100, a transdermal sampling andanalysis device200 may employ more than onedisruptor202. Thedisruptors202 may be configured in a way to disrupt the skin cells and allow the flow of biological samples over the counter and workingelectrodes208,210 of the transdermal sampling andanalysis device200. By increasing the number ofdisruptor202 sites, a larger volume of biological sample may be obtained in a shorter amount of time. This may result in a lessening of the experienced sensation or discomfort experienced by the subject. Additional biological samples obtained from the subject may enable a transdermal sampling andanalysis device200 to more accurately analyze the biological samples.

In the various embodiments, the transdermal sampling andanalysis device200 may include areservoir212 used to collect the biological samples that flow from the capillary-like channels of the skin. Thereservoir212 may be created by using processes and methods know in the art, such as by etching or arranging the transdermal sampling andanalysis device200 components in a manner to create areservoir212. For example, to create thereservoir212, photoresist material may be applied to the first surface of thesubstrates214 and patterns may be etched into the photoresist material to form thereservoir212. Photoresists and their uses are well known in the art.

In an embodiment, thereservoir212 may have a depth of about 20 μm to 100 μm. In a further embodiment, thereservoir212 may have a depth of about 50 μm to 100 μm. In a preferred embodiment, thereservoir212 may have a depth of about 30 μm. In a more preferred embodiment, thereservoir212 may have a depth of about 60 μm.

Thereservoir212 may be created in a location where it can collect the biological samples that flow out of the capillary-like channels of the disruptedskin100. Since thedisruptor202 creates the capillary-like channels in theskin100 from where biological samples flow, thereservoir212 may be positioned under or near thedisruptor202 to enable the transdermal sampling andanalysis device200 to collect the flowing biological samples. Thereservoir212 may comprise acollection reservoir212aformed generally to surround thedisruptor202 and asensing chamber212bformed generally to contain the biological sample around the sensing elements such as counter and workingelectrodes208,210. Thesensing chamber212bportion of thereservoir212 may contain the biological samples at one location where the samples may be analyzed by reacting with a biologically reactive element and interacting with thesensors208,210. Thereservoir212 may further prevent the biological samples from flowing to other components of the transdermal sampling andanalysis device200 not configured to analyze the obtained samples.

To further guide the movement of the biological samples in thereservoir212 and over the counter and workingelectrodes208,210,channels222 may be created. In an embodiment,channels222 may be formed usingchannel support structures220 positioned in thereservoir212 to facilitate and optimize the movement of the biological sample and the interactions of the sensors with the collected biological samples. Thereservoir212 andchannels222 may be created in a variety of shapes. For example, thereservoir212 may be square, triangle, trapezoid, rectangle or circle and thechannels222 may be linear or circular.

FIGS. 10A-10E illustrate top views of embodiment transdermal sampling andanalysis devices200 withdifferent reservoir212 andchannel222 shapes and configurations.FIG. 10A illustrates a top view of an embodiment transdermal sampling andanalysis device200 with a square shapedreservoir212, wherein the counter and workingelectrodes208,210 may be positioned withinreservoir212 and onedisruptor202 may be also positioned withinreservoir212.FIG. 10B illustrates a top view of an embodiment transdermal sampling andanalysis device200 with a trapezoid shapedreservoir212, the inter-digited counter and workingelectrodes208,210 anddisruptor202 may be all positioned within the trapezoidal shapedreservoir212.FIG. 10C illustrates a top view of an embodiment transdermal sampling andanalysis device200 with a rectangular shapedreservoir212, the inter-digited counter and workingelectrodes208,210 anddisruptor202 may be all positioned within the rectangular shapedreservoir212.FIG. 10D illustrates a top view of an embodiment transdermal sampling andanalysis device200 with a narrow rectangle shapedreservoir212, the inter-digited counter and workingelectrodes208,210 anddisruptor202 may be all positioned within the narrow rectangularshaped reservoir212.

FIG. 10E illustrates a top view of an embodiment transdermal sampling andanalysis device200 with a rectangular shapedreservoir212, twocounter electrodes208 and one workingelectrode210 with inter-digitations and positioned in thereservoir212 and adisruptor202 also located in thereservoir212. Longnarrow channels222 may be formed using several long channel supports220 arranged in a parallel orientation with one another. Thelong channels222 may function to facilitate the flow from where the biological samples away from thedisruptor202 and over the counter and workingelectrodes208,210 via capillary action.

Channel supports220 may be employed for different purposes. For example, since a subject's skin comes into contact with the side of the transdermal sampling andanalysis device200 on which biological samples may be collected, theskin100 may flex and dip in to thereservoir212 and prevent the flow of the biological samples to the counter and workingelectrodes208,210. Channel supports220 may be used to prevent the skin from blocking the flow of the biological sample to the counter and workingelectrodes208,210 by physically lifting the subject'sskin100 off of the transdermal sampling andanalysis device200 surface. Channel supports220 may further facilitate an even flow of the biological sample over the entire surfaces of the working and thecounter electrodes208,210.

In addition, the capillary force imparted by the channel supports220 may be adjusted by varying the shape, structure, and hydrophilicity of the constituent materials of the channel supports. By selecting different materials from which to form the channel supports220, the rate of flow of biological sample across the reservoir and surface of the counter and workingelectrodes208,210 may be altered. By selecting materials having greater hydrophilic characteristics the rate of flow across the reservoir may be augmented by the increase in surface tension between the biological sample and the supports of the hydrophilic channel supports220. Thus, by choosing a material with a greater hydrophilic property from which to form thechannel support220, the flow rate of the biological sample to cover the counter and workingelectrodes208,210 may be increased, which in turn minimizes the volume of biological sample needed to complete an accurate analysis. The relative hydrophilic characteristic of a material is measured by its wetting angle. Materials suitable for thechannel support220 may have a wetting angle of less than 40° and more preferably less than 20°. By using materials having such hydrophilic characteristics, the sampled fluid may be drawn by capillary action and hydrophilicity along the channel supports220 and to the back of the sensing chamber. Consequently, any trapped air within the sensing chamber or along thechannels222 formed between channel supports220 may be directed back toward thedisruptor202.

Moreover, alternative configurations of the channel supports may increase the surface area of thechannel support220 support that comes into contact with the biological sample. By increasing the surface area of thechannel support220 support, an increase on the hydrophilic action may be realized.

In still further alternative configurations, by reducing the space between channel supports220 at a desired location within the sensing chamber, capillary action may be increased. Consequently, the sampled fluid preferentially fills the sensing chamber. Capillary forces between structures within the remainder of the sensing chamber subsequently draw fluid from the first reservoir until the remainder of the sensing chamber is filled.

FIG. 11A illustrates an alternative embodiment of the transdermal sampling andanalysis device200. Similar to the embodiment shown inFIGS. 10A-10E, the embodiment transdermal sampling andanalysis device200 shown inFIG. 11A includes adisruptor202 having a serpentine configuration. Thedisruptor202 may be positioned within acollection reservoir212a. Leads capable of coupling thedisruptor202 to a voltage/current source may be extended to the corners of the transdermal sampling andanalysis device200. Thedisruptor202 may be also positioned within ahole1304 in a lid layer so that thedisruptor202 may be exposed to and may directly contact the subject's skin for disruption of the stratum corneum and the production of a biological fluid sample. Thecollection reservoir212aportion ofreservoir212 may be interconnected with asensing chamber212bportion ofreservoir212. Thesensing chamber212bportion contains the produced biological fluid sample over counter and workingelectrodes208,210. The produced biological fluid sample may be directed over the entire surface of counter and workingelectrodes208,210 viachannels222 formed between channel supports220. Anoptional reference electrode211 may be also shown inFIG. 11A. Thedisruptor202, counter and workingelectrodes208,210 andoptional reference electrode211 may be all formed on a substrate layer214 (not shown inFIG. 11A). Channel supports220 may be formed above the counter and workingelectrodes208,210 andoptional reference electrode211 in a spacer layer. The lid layer may be then adhered to the space layer above the channel supports220.

As discussed above, the channel supports may be formed of hydrophilic materials having a wetting angle of less than 40° and more preferably less than 20° to induce a capillary action force and draw the generated fluid sample to the upper regions of thesensing chamber212bportion. In addition, by varying the dimensions along the vertical axis of thechannels222, the capillary action may be increased, further forcing the generated fluid sample to the upper regions of thesensing chamber212bportion. As shown inFIG. 11A, the dimension ofchannels222 may be smaller in section A as compared to the dimension ofchannels222 in section B. Consequently, a greater capillary action force may be imparted on the generated fluid sample due in large part to the increased contact with the constituent hydrophilic material of channel supports220.Optimal channel222 widths have been found to range from 70 μm to less than 50 μm, and most preferably less than 30 μm.

FIG. 11B illustrates another alternative embodiment of the transdermal sampling andanalysis device200, wherein the dimensions of each of thechannels222 along the horizontal axis may be varied. As shown inFIG. 11B, thechannels222 shown between channel supports220 in region A may be narrower than thechannels222 shown between channel supports220 in region B. In doing so, the generated fluid sample may be directed up through thechannels222 in region A on the left of thedevice200 faster than the channels in region B on the right of thedevice200. Thus, any trapped air in thechannels222 that might prevent the generated fluid sample from completely covering thesensing electrodes208,210 insensing chamber212bmay be effectively systematically pushed from one side of thesensing chamber212bportion to the other so as to avoid trapping the air. Since a largervolume sensing chamber212bportion requires a relatively large fluid sample to completely fill thesensing chamber212bportion and insure complete coverage across counter and workingelectrodes208,210, the volume of thesensing chamber212bportion may be varied. Moreover, larger volumes of fluid samples require more time to generate. Thus, optimal volumes for thesensing chamber212bportion have been determined to be approximate 100 nanoliters (nl), and more preferably less than 20 nl, and most preferably 10 nl.Sensing chamber212bportion widths may be smaller than 500 um wide×1 mm long. Preferable dimensions may be below 250 um wide, 500 um long. Similarly, the size of thecollection reservoir212aportion may also impact the ability to obtain a viable fluid sample. The diameter of thecollection reservoir212amay be less than 1 mm and preferably between 500 and 800 μm.

FIGS. 12A-12C illustrate differentembodiment channel support220 support configurations which offer varying amounts of surface area.FIG. 12A illustrates a cross-sectional view of several channel supports220(12A) arranged in parallel orientation. The channels supports220(12A) may form a contact angle of 90° with thesubstrate214. The space between two channel supports220(12A) may create thechannels222. As the transdermal sampling andanalysis device200 comes into contact with theskin100, the skin may rest on top of the channel supports220(12A) and dip into thechannels222. If the distance between the two channel supports220(12A) is too large,skin100 may block thechannel222 by dipping far into it and touching the surface of thereservoir212. If the distance of the channel supports220(12A) is too small, the channel supports220(12A) may effectively block a sufficient flow of the biological sample to the counter and workingelectrodes208,210.

FIG. 12B illustrates a cross-sectional view of several channel supports220(12B) arranged in parallel orientation. The channels supports220(12B) may form a contact angle greater than 90° with thesubstrate214. The angled nature of the channel support220(12B) supports increases the surface area channel support220(12B) support, relative to channel supports220(12A) shown inFIG. 12A. As discussed above, the increased surface area increases the amount of interaction between the channel support220(12B) hydrophilic material and the biological sample. As a result, the flow of biological sample may be increased through thechannels222 relative to the configuration shown inFIG. 12A.

FIG. 12C illustrates an alternative cross-sectional view of several channel supports220(12C) which increases, relative to channel supports220(12A) shown inFIG. 12A, the surface area of the channel support220(12C) material that may come into contact with the biological sample, which providing increased support to prevent the subject's surrounding skin from occluding the flow of the biological sample from the counter and workingelectrodes208,210. However, the configuration shown inFIG. 12C may decrease the volume of biological sample allowed to flow in each channel222(12C), unless the distance between channel supports220 may be increased as the volume of the channels222(12C) may be decreased relative to the volume of the channels222(12A) shown inFIG. 12A.

Another parameter of the channel supports220 that may affect the functionality of the transdermal sampling andanalysis device200 may be the height of the channel supports220 as compared to the distance the channel supports220 may be positioned from thedisruptor202. If long channel supports220 may be positioned too close to thedisruptor202, the height of thechannel support220 may prevent theskin100 from coming into contact with thedisruptor202 when the transdermal sampling andanalysis device200 may be placed next to theskin100. If short channel supports are positioned too far from thedisruptor202, the deformable subject'sskin100 may dip into a gap1202 created between thechannel support220 anddisruptor202 and block the flow of the biological samples to the sensor electrodes.

FIG. 13 illustrates a cross-sectional view of an embodiment transdermal sampling andanalysis device200, showing a preferred method of determining the ratio between the height of achannel support220 and its distance from thedisruptor202. The preferred distance to height ratio between thedisruptor202 and the channel supports220 may be determined by using the ratio of the sides of a 30°-60°-90°triangle1204. The 30°-60°-90°triangle1204 side “a” may be used to determine the height of thechannel support220. The 30°-60°-90°triangle1204 side “b” may be used to determine the distance of thechannel support220 to thedisruptor202. In an embodiment, the side “b” (i.e., the distance of the channel supports from the disruptor202) may be about 0 μm to 30 μm. In a preferred embodiment, the side “b” may be about 30 μm and side “a” may be about 50 μm.

The biological sample collected by an embodiment transdermal sampling andanalysis device200 may escape from thereservoir212 before it comes into contact with the sensing electrodes. To ensure that the transdermal sampling andanalysis device200 has sufficient sample to perform the required analysis, different methods may be employed. For example,channels222 may be used to facilitate the movement of the biological sample over the sensing electrodes;hydrophilic channel support220 material may be used to hold the biological samples attached to the channel supports220 for a longer period of time; thedisruptor202 may apply heat to the skin for a longer period of time to keep the capillary-like opening of the skin open longer to obtain a larger amount of the biological sample; and/or a lid may be placed over thereservoir212 to keep the biological sample from evaporating.

In an embodiment, to more efficiently collect and maintain the biological fluid from the subject, a lid may be placed on the exposed side of the transdermal sampling andanalysis device200.FIG. 14A illustrates a top view of an embodiment transdermal sampling andanalysis device200 before alid1302 may be placed over the transdermal sampling andanalysis device200. The transdermal sampling andanalysis device200 includes counter and workingelectrodes208,210, adisruptor202, and areservoir212 encompassing thedisruptor202 and counter and workingelectrodes208,210. Air vents224 may be shown coupled to thereservoir212 to allow air to escape as the biological sample flows to fill the reservoir from thedisruptor202 site to the top of thereservoir212. Aspacer layer1408 may be formed over portions of the counter and workingelectrodes208,210. Thespacer layer1408 may effectively form the walls ofreservoir212.

FIG. 14B B illustrates the same transdermal sampling andanalysis device200 after alid1302 may be placed over the elements of the transdermal sampling andanalysis device200 andspacer layer1408. Thelid1302 partially covers thereservoir212 to encapsulate the obtained biological sample. The lid effectively creates a closed volume defined by thereservoir212 and thelid1302. Without the use of a lid, the biological sample may be contained within thereservoir212 by applying sufficient pressure to the transdermal sampling andanalysis device200 against the subject skin. In effect the subject skin acts as a lid to contain the biological sample within thereservoir212. When alid1302 is placed over thereservoir212, it may be necessary to includeair vents224 to allow air from escaping as the biological sample flows from one side of thereservoir212 to another.

Thelid1302 may cover the entire surface of the transdermal sampling andanalysis device200 with the exception of thedisruptor202. In an embodiment, ahole1304 may be carved in thelid1302 to allow thedisruptor202 to be exposed while the other parts of the transdermal sampling andanalysis device200 may be covered. The hole may allow thedisruptor202 to come into contact with theskin100 thus effecting adequate heating of the stratum corneum to cause disruption. Thehole1304 may also guide the biological fluid to flow into thereservoir212. In a preferred embodiment, thehole1304 has a diameter (or width) dimension of about 500 μm.

Thelid1302 that may be placed over thereservoir212 may be made of a material such as plastic, metal, ceramic, or polymer. In a preferred embodiment, thelid1302 may be made from a polymer. Thelid1302 thickness should be minimal to enable contact between the user's skin and thedisruptor202 with a minimalfirst reservoir212adiameter. However, thelid1302 should be thick enough to maintain chamber integrity in the presence of the pressure required to achieve intimate contact between the user's skin and disruptor. The lid1302 (and adhesive layer adhering thelid1302 to thespacer layer1408 discussed in more detail below with respect toFIG. 15A-15C) may have a thickness of about 10 μm to 75 μm. Preferably, thelid1302 may have thickness of about 15-30 μm. The inner surface of thelid1302 may be hydrophilic, preferably having a wetting angle of less than 50°, and more preferably less than 20°.

In an embodiment, instead of creating thechannels222 in thereservoir212,channels222 may be formed on the side of thelid1302 that may be closer to the substrate when thelid1302 is placed on the transdermal sampling andanalysis device200. In such a configuration, thereservoir212 may be constructed withoutchannels222. Thelid1302 may include channel supports220 andchannels222. Once thelid1302 is positioned on the transdermal sampling andanalysis device200, the channels supports220 of thelid1302 may createchannels222 in thereservoir212. This may be useful in the manufacturing process, wherechannels222 created in thereservoir212 may clog when the biologically reactive element is applied to the surface of theelectrodes208,210. By including the channel supports220 in thelid1302, the biologically reactive element may be applied to the surface of thereservoir212. Thechannels222 may then be formed on top of the biologically reactive elements in thereservoir212 once thelid1302 is positioned on the transdermal sampling andanalysis device200.

FIG. 15A illustrates a top view of an embodiment transdermal sampling andanalysis device200. The transdermal sampling and analysis device may include a substrate214 (shown inFIGS. 15B and 15C), adisruptor202 located within acollection reservoir212aportion, areservoir connector channel1402 which connects thecollection reservoir212aportion to asensing chamber212bportion. Thesensing chamber212bmay be disposed over (or under) one workingelectrode210 and twocounter electrodes208. Thesensing chamber212bmay allow the biological sample to collect over the counter and workingelectrodes208,210, respectively. A biologically reactive element (not shown) may also be applied in the sensing chamber and over the counter and workingelectrodes208,210. The counter and workingelectrodes208,210 may be connected to electricalconductive paths206a,206b, respectively. Avent hole224 may be present at the distal end of thesensing chamber212bto allow air to escape as the biological sample moves from thecollection reservoir212ato thesensing chamber212bthrough thereservoir connector channel1402.

The width of thereservoir connector channel1402 may affect the distance between thedisruptor202 and the counter and workingelectrodes208,210. For example, a narrowreservoir connector channel1402 may allow small amounts of fluid to be directed from thecollection reservoir212ato thesensing chamber212b. A widereservoir connector channel1402 may be used for directing larger amounts of biological sample from thecollection reservoir212ato thesensing chamber212b. Thus, to direct small amounts of fluid from the first to sensing chamber in a transdermal sampling andanalysis device200 with a widereservoir connector channel1402, the distance between thedisruptor202 and the counter and workingelectrodes208,210 may be minimized as compared to a transdermal sampling andanalysis device200 with a narrowreservoir connector channel1402. In a preferred embodiment, thereservoir connector channel1402 may be 30-100 μm wide and 200-500 μm long.

As mentioned above, the transdermal sampling andanalysis device200 may further include alid1302 with alid opening1304. Thelid opening1304 may be located over thedisruptor202 to allow thedisruptor202 to come into direct contact with the subject's skin and as well as provide an open path for interstitial fluid to flow out of the stratum corneum and into thecollection reservoir212a. Thedisruptor202 may be coupled to a signal generator (not shown). Theopening1304 in thelid1302 exposes thedisruptor202 and allow contact between thedisruptor202 and the users' skin should be smaller in diameter than thecollection reservoir212ato enhance the collection of the fluid sample. For a 750μm collection reservoir212adiameter, thelid opening1304 should be between 200 μm and 1 mm, preferably between 300-700 μm, and most preferably 500 μm.

FIG. 15B illustrates a cross-sectional view of the transdermal sampling andanalysis device200 along reference points AA′ andreference line1404. The arrows on thecross-section line1404 shows the direction of the cross-sectional view. The transdermal sampling andanalysis device200 may be comprised of several layers including asubstrate layer214, aspacer layer1408 and alid layer1302. Referring toFIG. 15B, thelid1302 may be adhered to thespacer layer1408 using anadhesive layer1303. The total thickness of thelid1302 withadhesive layer1303 should be between 10-75 μm, and preferably between 15-30 μm. Thelid adhesive layer1303 may itself have a thickness of between 5-20 μm, and preferably between 3-10 μm. If the thickness of the adhesive layer is too thick, the adhesive may flow into thefirst reservoir212a,sensing chamber212bas well asreservoir connector channel1402 when applied. However, if the thickness of theadhesive layer1303 is insufficient, it may not flow and completely seal thelid1302 to thespacer1408. In addition, theadhesive layer1303 should be sufficiently flat when applied so as to seal the surface of thespacer layer1408 with minimal flow upon application. The surface of the adhesive layer should have an RMS roughness value of Ra below 3 μm, and preferably below 1 μm. Theadhesive layer1303 should exhibit hydrophilicity, having a wetting angle below 40° and preferably below 20°. Theadhesive layer1303 material should exhibit flow characteristics having Tg between 0 and 50° C., preferably between 0 and 30° C., and most preferably between 10 and 20° C.

Thespacer layer1408 may separate thesubstrate layer214 and thelid layer1302. Thefirst reservoirs212aandsensing chamber212band thereservoir connector channel1402 may be created by thespacer layer1302 using methods as described above. Thespacer layer1408 may be 10 and 70 μm thick and may be selected from a material such as polymer or ceramic. It should be noted that if the thickness of thespacer layer1408 is too thick, the user's skin will be effectively spaced away from thedisruptor202 formed on asubstrate214. As the diameter of thefirst reservoir212amay be decreased, it becomes increasingly difficult for the user's skin to deflect into thefirst reservoir212aand come into contact with thedisruptor202. Accordingly, as the diameter of thefirst reservoir212amay be decreased, the thickness of thespacer layer1408 must also be decreased. The thickness of thespacer layer1408 may be between 10 and 50 μm, and most preferably between 15 and 30 μm for a first reservoir having a diameter of 750 μM.

Thecollection reservoir212amay be located within thehole1304 and surrounding thedisruptor202 to allow the biological sample to collect in thecollection reservoir212a. As shown inFIG. 15B, the width of thecollection reservoir212amay be slightly larger than the width of thehole1304 in thelid1302. Electricallyconductive paths206a,206bmay be located between thesubstrate layer214 andspacer layer1302. The electricallyconductive path206aconnects to thecounter electrode208 and the electricallyconductive path206bconnects to the workingelectrodes210. It may be noted that the thickness of the electricallyconductive paths206aand206bmay be such that in comparison to the thickness of thesubstrate214,spacer1408 andlid1302 layers, the conductive path layers may not be seen in the cross sectional view.

FIG. 15C illustrates a cross-sectional view of the transdermal sampling andanalysis device200 along reference points BB′ andreference line1406. The arrows on thecross-section line1404 shows the direction of the cross-sectional view. At this cross-section, the transdermal sampling andanalysis device200 may include asubstrate layer214, aspacer layer1408 and alid layer1302. Thespacer layer1408 may form the boundaries of thesensing chamber212b. By adhering thelid1302 fully over thesensing chamber212b, the biological sample may be prevented from evaporating or pouring out of the transdermal sampling andanalysis device200 and adequately react with the biologically reactive element in thesensing chamber212b.

FIG. 16 is a perspective view of an embodiment transdermal sampling andanalysis device200 using a raiseddisruptor202. The transdermal sampling andanalysis device200 shown inFIG. 16 is shown without a lid. The transdermal sampling andanalysis device200 is shown to have a raiseddisruptor202. Raising thedisruptor202 may assure good contact of thedisruptor202 to theskin100, which may be advantageous with increasingchannel support220 height. Another advantage of using a raiseddisruptor202 may be that it acts much like the channel supports which displace theskin100 from the surface of the electrodes so that the biological sample may flow freely over the surface of the electrodes. This configuration may also allow for creation of channels in the gap between thecoils802 ofserpentine disruptors202 which assist in increasing the flow of the obtained biological sample. Aspacer layer1408 may disposed on thesubstrate214 to form areservoir212 encompassing the counter and workingelectrodes208,210 so that a biological fluid sample generated when thedisruptor202 disrupts the subject's skin may be contained within thereservoir212 and over the counter and workingelectrodes208,210. Any of a variety of manufacturing techniques may be employed to form the raised disruptor surface. For example, the layer of material used to form the disrupter may be deposited in a series of deposition steps to build up a sufficient layer before excess material may be etched away in a photolithography process. Alternatively, the deposition process itself may be used to continuous deposit material in the form of the disruptor to build up the raised disruptor structure.

The transdermal sampling andanalysis devices200 of the various embodiments may be manufactured using different methods and materials. Manufacturing methods for an embodiment transdermal sampling andanalysis device200 may be disclosed in the related International Application Number PCT/US2006/023194, filed Jun. 14, 2006, entitled “Flexible Apparatus and Method for Monitoring and Delivery,” which claims priority to the International Application Number PCT/US2005/044287, entitled “Apparatus and Method for Continuous Real-Time Trace Bimolecular Sampling, Analysis and Deliver,” filed on Dec. 9, 2005, which are attached hereto as Appendices A and B. The manufacturing of an embodiment transdermal sampling andanalysis device200 is also disclosed in the publication entitled “Novel Non-Intrusive Trans-Dermal Remote Wireless Micro-Fluidic Monitoring System Applied to Continuous Glucose and Lactate Assays for Casualty and Combat Readiness Assessment” by John F. Currie, Michael M. Bodo and Frederick J. Pearce, RTO-MP-HFM-109:24-1, Aug. 16, 2004. A copy of the publication is attached hereto as Appendix C. The entire contents of all of the related applications and publication are incorporated by reference herein.

An embodiment device may be manufactured using materials and equipment commonly used in the micro-fabrication and bio-sensing industries. Conductive material, of which disruptor, sensing electrodes and interconnects may be formed, may be deposited on clean substrate material. Disruptor, sensing electrodes, and interconnects may then be patterned by a photolithographic process well known in the art (e.g., apply photoresist, dry, expose pattern in photoresist, develop photoresist, etch metal, strip photoresist). Spacer layer may be formed of photo-sensitive polymer or other technique well known in the art (coat to desired thickness, dry, expose pattern, develop, dry, bake). Organic residue remaining on electrodes from the above processing may be removed by oxygen plasma treatment well known in the art. An analyte sensing layer may be applied to sensing electrodes as known in the art Lid material may be produced by applying a thin layer of adhesive to a polymeric substrate such as polyester, polycarbonate, acetate, or the like, then cutting to size and shape by IR or excimer laser as well known in the art.

Glucose oxidase (GOD), an enzyme prototype, may be absorbed electrochemically onto a polypyrrole (PPy) layer using a potentiostat together with an electrolyte solution consisting of 0.1 M, each, of PPY and KCl at 0.8 V for 2 minutes. 0.1 M Ferricyanide and 8001 units/ml of GOD (18 micoliters GOD and 48 microliters K2FeCN6 in 10 ml phosphate buffer solution) may be further added in the electrolyte solution for the deposition of GOD. Selective deposition of PPy+GOD may be then done on one of the exposed electrodes of the transdermal sampling andanalysis device200. Chronoamperometric dose responses may be recorded and the results reveal that the sensor has a good linearity from 0 to 10 mM glucose with the sensitivity of 2.9 mA/mM. For the lactate sensor chips, the same process may be used except lactate oxidase was substituted for the GOD.

In an embodiment the transdermal sampling andanalysis device200 may be used to deliver substances into the capillary-like channels of theskin100. A substance may be loaded on the transdermal sampling andanalysis device200, preferably in an encapsulation. Heat applied to the skin creates capillary-like channels in the stratum corneum. The substance may then be delivered transdermally into the body through the capillary-like opening in the skin. Positive pressure may be required to deliver the substance into the body as interstitial fluid exits the body.

The transdermal sampling andanalysis device200 of the various embodiments may be packaged in a sealed and sterile container without any contaminants. The seal may be broken to access one transdermal sampling andanalysis device200 using an applicator. Once the transdermal sampling andanalysis device200 is taken out of the sealed packaging, it may be used as described above. The transdermal sampling and analysis device of the various embodiments may be disposable or reusable.

The transdermal sampling andanalysis device200 of the various embodiments may have a variety of different uses including monitoring for viability and functionality of organs and tissues prepared and stored for surgical implantations; monitoring entire chemical panels for individuals, patients, or populations at risk; monitoring for critical care, shock, trauma and resuscitation; monitoring for chronic critical diseases; monitoring for early detection of diseases; monitoring for response to therapeutic treatments; and gene therapy.

The transdermal sampling andanalysis device200 of the various embodiments may also be used to analyze biological samples that have already been collected from samples such as food, water, air, whole blood, urine, saliva, chemical reactions or cultures.

The transdermal sampling andanalysis device200 of the various embodiments may be applied to theskin100 of a subject using anapplicator device1700. Theapplicator device1700 may be configured to take different shapes and designs. In an exemplary embodiment, as illustrated inFIG. 17, theapplicator device1700 may be configured to have a cylindrical design with ahead1702 and abody1704. Thehead1702 may be configured to engage an embodiment transdermal sampling andanalysis device200 and couple it to both a voltage source as well as to a sensing unit and display. Avoltage source1718 may be provided in the form of a battery or an alternating current adapted to accept an alternating current voltage signal. For example, a user may load theapplicator device1700 by picking-up a transdermal sampling andanalysis device200 for measuring body parameters and unloading by discarding the transdermal sampling andanalysis device200 when the required parameters may be obtained or when the transdermal sampling andanalysis device200 is no longer functional.

Thebody1704 may include aprocessor1706 coupled to adisplay monitor1708 for displaying data to the user, amemory1710 for storing processed data received from the transdermal sampling andanalysis device200, and atransceiver1712 for transmitting information from theapplicator device1700 or for receiving data. Theprocessor1706 may also include a digital signal processor which modifies the voltage source to produce a voltage signal having the appropriate duty cycle before application across the terminals of the embodiment disruptor. Thebody1704 may also include anantenna1714, used to transmit and receive radio frequency signals, coupled to thetransceiver1712. Alternatively, theapplicator1700 may include a data communication port1716 such as USB or FireWire® which enables the applicator to transfer data over a communication cable to another device.

Theprocessor1706 may be configured by software to receive signals from the transdermal sampling andanalysis device200 and convert the signals to user ascertainable information. The user ascertainable information may be displayed on thedisplay monitor1708. The processed data may be stored inmemory1710. For example, if the transdermal sampling andanalysis device200 is configured to determine blood glucose levels, theapplicator device1700 may be configured to receive electrical signals generated by the transdermal sampling andanalysis device200 and convert the signals, using theprocessor1706, to user ascertainable information such as a numeric glucose level. The information may be stored in thememory1710. The numeric glucose level may be displayed on thedisplay monitor1708. In this example, the blood glucose levels are measured to be “97” which is displayed in thedisplay monitor1708.

Thebody1704 may further include atransceiver1712 coupled to theprocessor1704 and anantenna1714 to wirelessly transmit data to other devices or receive data. For example, theapplicator device1700 may transmit data obtained from a subject to a remote server1720. Theapplicator device1700 may store the processed data inmemory1710 and transmit the data either continuously or intermittently to other devices.

FIG. 18 illustrates a component block diagram for a transdermal sampling andanalysis device system1800 according to an embodiment. Once the data is collected by the transdermal sampling andanalysis device200 and theapplicator device1700, the data may be transmitted to the other components of the transdermal sampling andanalysis device system1800 for storage/analysis. For example, the data may be transmitted to anexternal transceiver1802 which in turn may relay the data to aremote server1804 for storage and/or analysis. Theremote server1804 may receive and store the transmitted information as part of the subject's records, such as medical records; or theserver1804 may be configured to receive the data for conducting research. In an alternative example, theserver1804 may include a built-in transceiver using which it may receive and/or transmit data wirelessly.

In a further embodiment, data received and stored by anapplicator device1700 may be transmitted to aremote computing device1806. Theremote computing device1806 may receive and store the transmitted data and display it on the monitor and/or perform further analysis of the data.

The remote devices (i.e.,server1804 and computing device1806) may communicate with other remote devices, such asserver1810 by using different communication means such as theInternet1808. For example, information received from the transdermal sampling andanalysis device200 may be transmitted to the remote devices using theapplicator device1700. The remote devices may in turn transmit data to other devices via theInternet1808 for storage or further analysis.

In an exemplary embodiment, as illustrated inFIG. 19A, several transdermal sampling andanalysis devices200 may be arranged in asterile kit1902. In this example, the transdermal sampling andanalysis devices200 may be arranged next to one another, each in a sterile compartment, in the kit. Theapplicator device1700 may be configured to load one transdermal sampling andanalysis device200 at a time from different compartments of thekit1902 to ensure that the additional transdermal sampling andanalysis devices200 remain sterile and ready for future use.

In a further embodiment, as illustrated inFIG. 19B, the transdermal sampling andanalysis devices200 may be arranged in a sterile stack in akit1904 that may be cylindrical in shape. In this example, theapplicator device200 may be configured to load by contacting theapplicator device200 to the transdermal sampling andanalysis device200 which may be at the top of the sterile stack in thekit1904. The transdermal sampling andanalysis devices200 may be stacked directly on top of one another in thekit1904 or may be separated by a separator material. As transdermal sampling andanalysis devices200 may be used to obtain a biological sample, the transdermal sampling andanalysis device200 may be ejected from the applicator device and disposed above.

FIG. 19C illustrates a further embodiment method for loading and unloading transdermal sampling andanalysis devices200 on theapplicator device1700. In this embodiment, akit cartridge1906 including several transdermal sampling andanalysis devices200 stacked in a vertical configuration may be loaded on to theapplicator device1700. Theapplicator device1700 may have alever1908 which may allow the user to load or unload transdermal sampling andanalysis devices200 onto thetip1912 of theapplicator device1700. For example, once thekit cartridge1906 may be loaded onto theapplicator device1700, the user may push down thelever1908 in the direction of thearrow1910 to load thetip1912 of theapplicator device1700 with a transdermal sampling andanalysis device200. Once the transdermal sampling andanalysis device200 is used up, it may be unloaded by simply pushing it out of theapplicator device1700 by pushing thelever1908 in the direction of thearrow1910 and discarding it. This process may continue until the last transdermal sampling andanalysis device200 is used. Once the last transdermal sampling andanalysis device200 is used, thekit cartridge1906 may be changed with one that includes new transdermal sampling andanalysis devices200.

In an embodiment illustrated inFIG. 20, after loading anapplicator device1700 with a transdermal sampling andanalysis device200 from akit1902,1904,1906 theapplicator device1700 may apply the transdermal sampling andanalysis device200 to theskin100 of a subject. The transdermal sampling andanalysis device200 may be applied to theskin100 by moving theapplicator device1700 in the direction of thearrow2004 towards theskin100. Once in contact with theskin100, the transdermal sampling andanalysis device200 may draw interstitial fluid and generate signals which may be transmitted to theprocessor1708.

A number of the embodiments described above may be implemented with any of a variety of remote server devices, such as theserver2100 illustrated inFIG. 21. Such aserver2100 typically includes aprocessor2101 coupled tovolatile memory2102 and a large capacity nonvolatile memory, such as adisk drive2103. Theserver2100 may also include a floppy disc drive and/or a compact disc (CD) drive2106 coupled to theprocessor2101. Theserver2100 may also include a number ofconnector ports2104 coupled to theprocessor2101 for establishing data connections withnetwork circuits2105.

The embodiments transdermal sampling and analysis device data described above may also be transmitted or coupled to any of a variety of computers, such as apersonal computer2200 illustrated inFIG. 22, for further monitoring, storage or manipulation. Such apersonal computer2200 typically includes aprocessor2201 coupled tovolatile memory2202 and a large capacity nonvolatile memory, such as adisk drive2203. Thecomputer2200 may also include a floppy disc drive and/or a compact disc (CD) drive2206 coupled to theprocessor2201. Typically thecomputer2200 will also include a pointing device such as amouse2209, a user input device such as akeyboard2208 and adisplay2207. Thecomputer2200 may also include a number ofnetwork connection circuits2204, such as a USB or FireWire®, coupled to theprocessor2201 for establishing data connections to theapplicator1700. In a notebook configuration, the computer housing includes thepointing device2209,keyboard2208 and thedisplay2207 as is well known in the computer arts.

Theprocessor1706,2101,2201 may be any programmable microprocessor, microcomputer or multiple processor chip or chips that can be configured by software instructions (applications) to perform a variety of functions, including the functions of the various embodiments described herein. In some mobile devices,multiple processors1706,2101,2201 may be provided, such as one processor dedicated to wireless communication functions and one processor dedicated to running other applications. Typically, software applications may be stored in theinternal memory1710,2102,2202 before they are accessed and loaded into theprocessor1706,2101,2201. In some mobile devices, theprocessor1706,2101,2201 may include internal memory sufficient to store the application software instructions. The internal memory of the processor may include a secure memory (not shown) which is not directly accessible by users or applications and that may be capable of recording MDINs and SIM IDs as described in the various embodiments. As part of the processor, such a secure memory may not be replaced or accessed without damaging or replacing the processor. In somedevices200,2100,2200, additional memory chips (e.g., a Secure Data (SD) card) may be plugged into the device and coupled to theprocessor1706,2101,2201. In many devices, theinternal memory1710,2102,2202 may be a volatile or nonvolatile memory, such as flash memory, or a mixture of both. For the purposes of this description, a general reference to memory refers to all memory accessible by theprocessor1706,2101,2201, includinginternal memory1710,2102,2202, removable memory plugged into the device, and memory within theprocessor1706,2101,2201 itself, including the secure memory.

The various illustrative logical blocks, modules, circuits, and algorithm steps described in connection with the aspects disclosed herein may be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality. Whether such functionality may be implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. Skilled artisans may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present invention.

The hardware used to implement the various illustrative logics, logical blocks, modules, and circuits described in connection with the aspects disclosed herein may be implemented or performed with a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor may be a microprocessor, but, in the alternative, the processor may be any conventional processor, controller, microcontroller, or state machine. A processor may also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. Alternatively, some steps or methods may be performed by circuitry that is specific to a given function.

In one or more exemplary aspects, the functions described may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functions may be stored on or transmitted over as one or more instructions or code on a computer-readable medium. The steps of a method or algorithm disclosed herein may be embodied in a processor-executable software module executed which may reside on a tangible non-transitory computer-readable medium or processor-readable medium. Non-transitory computer-readable and processor-readable media may be any available media that may be accessed by a computer or processor. By way of example, and not limitation, such computer-readable media may comprise RAM, ROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, or any other medium that may be used to carry or store desired program code in the form of instructions or data structures and that may be accessed by a computer. Disk and disc, as used herein, includes compact disc (CD), laser disc, optical disc, digital versatile disc (DVD), floppy disk, and blu-ray disc where disks usually reproduce data magnetically, while discs reproduce data optically with lasers. Combinations of the above should also be included within the scope of computer-readable media. Additionally, the operations of a method or algorithm may reside as one or any combination or set of codes and/or instructions on a non-transitory processor-readable medium and/or computer-readable medium, which may be incorporated into a computer program product.

The preceding description of the disclosed aspects is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these aspects will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other aspects without departing from the scope of the invention. Thus, the present invention is not intended to be limited to the aspects shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

While the invention has been described in detail with respect to specific embodiments thereof, it will be apparent to those skilled in the art that various alterations, modifications and other changes may be made without departing from the scope of the embodiments described herein. It is therefore intended that all such modifications, alterations and other changes be encompassed by the claims. Further, any reference to claim elements in the singular, for example, using the articles “a,” “an” or “the” is not to be construed as limiting the element to the singular.

Claims (69)

What is claimed is:

1. A transdermal sampling and analysis device comprising:

a substrate having a first side;

a disruptor mounted on the first side of the substrate, wherein the disruptor has a resistance of about 5 Ohms to about 50 Ohms and is configured to generate a localized heat capable of altering the permeability characteristics of barrier cells of an organism to become permeable when a voltage is applied across the disruptor;

a reservoir on the first side of the transdermal sampling and analysis device, wherein the reservoir comprises:

a collection portion configured to collect and contain a biological sample that is obtained through the permeable barrier cells; and

a sensing chamber configured with a plurality of channels formed between a plurality of channel supports;

a biological sensing element comprising at least two sensing electrodes mounted on the first side of the substrate, wherein the biological sensing element is configured to determine the levels of an analyte in the biological sample;

a lid configured to enclose the reservoir and the at least two sensing electrodes within a volume formed in the reservoir;

a spacer disposed on top of the substrate; and

a lid adhesive layer adhering the lid to the spacer, wherein the lid adhesive layer has a hydrophilic wetting angle that is less than 40°,

wherein the sensing chamber is configured to contain the biological sample around the at least two sensing electrodes, wherein the biological sample is directed over the surface of the at least two sensing electrodes by the plurality of channels.

2. The transdermal sampling and analysis device ofclaim 1, wherein the biological sensing element is an amperometric sensing element configured to measure a current generated across the at least two sensing electrodes carried by ions generated during a reaction between the analyte in the biological sample and a reactive agent coating the at least two sensing electrodes.

3. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is a flexible substrate.

4. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is made of a material selected from the group consisting of ceramic, plastic, metal and silicon.

5. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is made of a material with a coefficient of thermal expansion (CTE) of about 10 to 50 ppm/° C.

6. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is made of a material with a coefficient of thermal expansion (CTE) of about 20 ppm/° C.

7. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is made of a material with a coefficient of thermal conductivity (CTC) of about 0.05 to 1.1 W/m° K.

8. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is made of a material with a CTC of about 0.12 W/m° K.

9. The transdermal sampling and analysis device ofclaim 1, wherein the substrate is made from plastic.

10. The transdermal sampling and analysis device ofclaim 9, wherein the plastic substrate is annealed to prevent the plastic substrate from shrinking when heat is generated by the at least one disruptor mounted on the substrate.

11. The transdermal sampling and analysis device ofclaim 9, wherein the substrate is a polyimide.

12. The transdermal sampling and analysis device ofclaim 11, wherein the polyimide is Kapton™.

13. The transdermal sampling and analysis device ofclaim 1, wherein the at least one disruptor is made from a material selected from the group consisting of titanium, tungsten, stainless steel, platinum and gold.

14. The transdermal sampling and analysis device ofclaim 1, wherein the at least one disruptor is formed in a shape selected from the group consisting of serpentine, circular, linear, square, rectangular, trapezoidal, hexagonal and triangular.

15. The transdermal sampling and analysis device ofclaim 14, wherein the disruptor is formed in a serpentine shape.

16. The transdermal sampling and analysis device ofclaim 15, wherein the coils of the serpentine disruptor are at most 20 μm apart.

17. The transdermal sampling and analysis device ofclaim 1, wherein an area covered by the at least one disruptor has a 1:1 aspect ratio +/−50%.

18. The transdermal sampling and analysis device ofclaim 14, wherein the at least one disruptor has at least one side of about 100 μm in length.

19. The transdermal sampling and analysis device ofclaim 14, wherein the at least one disruptor has at least one side of about 200 μm in length.

20. The transdermal sampling and analysis device ofclaim 14, wherein the at least one disruptor has at least one side of about 400 μm in length.

21. The transdermal sampling and analysis device ofclaim 1, wherein the at least one disruptor delivers heat at a rate of about 3 W per mm².

22. The transdermal sampling and analysis device ofclaim 1, wherein the at least one disruptor delivers heat at a rate of more than about 1 W per mm²and less than about 10 W per mm².

23. The transdermal sampling and analysis device ofclaim 1, wherein the temperature of the at least one disruptor during heating is about 50° C to 150° C.

24. The transdermal sampling and analysis device ofclaim 1, wherein the temperature of the at least one disruptor during heating is 90° C to 110° C.

25. The transdermal sampling and analysis device ofclaim 1, wherein the voltage applied across the at least one disruptor is supplied by a direct current source.

26. The transdermal sampling and analysis device ofclaim 1, wherein the voltage applied across the at least one disruptor reaches a voltage potential of about 2 V.

27. The transdermal sampling and analysis device ofclaim 26, wherein the voltage applied to the disruptor is applied in a stepwise manner until the voltage potential is reached.

28. The transdermal sampling and analysis device ofclaim 1, wherein the biological sensing element is a biologically reactive element.

29. The transdermal sampling and analysis device ofclaim 1, wherein the analyte is glucose.

30. The transdermal sampling and analysis device ofclaim 1, wherein the biological sensing element is an electrochemical sensor.

31. The transdermal sampling and analysis device ofclaim 1, wherein the at least two sensing electrodes are made from a material selected from the group consisting of platinum, carbon, silver, and gold.

32. The transdermal sampling and analysis device ofclaim 1, wherein the at least two sensing electrodes comprise three or more inter-digitated electrodes.

33. The transdermal sampling and analysis device ofclaim 32, wherein the three or more inter-digitated electrodes comprising at least one working electrode and at least one counter electrode.

34. The transdermal sampling and analysis device ofclaim 1, wherein the reservoir has a depth of about 20 μm to 70 μm.

35. The transdermal sampling and analysis device ofclaim 1, wherein the reservoir has a depth of about 50 μm to 70 μm.

36. The transdermal sampling and analysis device ofclaim 1, wherein the reservoir has a depth of about 30 μm.

37. The transdermal sampling and analysis device ofclaim 1, wherein a width of the plurality of channels varies along the vertical axis.

38. The transdermal sampling and analysis device ofclaim 1, wherein the width of each of the plurality of channels is 30 μm.

39. The transdermal sampling and analysis device ofclaim 1, wherein:

the plurality of channels comprises a first end and a second end along a horizontal axis, wherein a width of adjacent channel is successively widened such that a most narrow channel is at the first end of the plurality of channels and a most wide channel is at the second end of the plurality of channels.

40. The transdermal sampling and analysis device ofclaim 1, wherein each of plurality of channel supports are configured to form a contact angle of greater than 90° when attached to the substrate.

41. The transdermal sampling and analysis device ofclaim 1, wherein each of the plurality of channel supports are formed from a material having a maximum wetting angle of 30°.

42. The transdermal sampling and analysis device ofclaim 1, wherein the transdermal sampling and analysis device is configured to obtain a volume of biological sample through the permeable barrier cells of less than 40 nl.

43. The transdermal sampling and analysis device ofclaim 1, wherein the transdermal sampling and analysis device is configured to obtain a volume of biological sample through the permeable barrier cells of less than 10 nl.

44. The transdermal sampling and analysis device ofclaim 28, wherein the biologically reactive element is selected from the group consisting of tissues, micro-organisms, organelles, cell receptors, enzymes, antibodies, nucleic acids, biologically derived material, bio-mimics, selective ion membranes.

45. The transdermal sampling and analysis device ofclaim 1, wherein the transdermal sampling and analysis device detects and measures a level of the analyte in the biological sample by using a sensing method selected from the group consisting of amperometry, coulometry, potentiometry and electrochemical impedance methods.

46. The transdermal sampling and analysis device ofclaim 28, wherein the biologically reactive element is selected from the group consisting of glucose oxidase and glucose dehydrogenase.

47. The transdermal sampling and analysis device ofclaim 1, wherein the lid is configured to expose the at least one disruptor to a user's skin.

48. The transdermal sampling and analysis device ofclaim 1, wherein the lid has a thickness of about 10 μm to 50 μm.

49. The transdermal sampling and analysis device ofclaim 1, wherein the lid is made from a material selected from the group consisting of plastic and metal.

50. The transdermal sampling and analysis device ofclaim 1, wherein the spacer has a thickness of about 10 μm to 70 μm.

51. The transdermal sampling and analysis device ofclaim 1, wherein the lid adhesive layer has a thickness of about 5 μm to 20 μm.

52. The transdermal sampling and analysis device ofclaim 1, wherein the lid adhesive layer and the lid have a combined thickness of about 10 μm to 75 μm.

53. The transdermal sampling and analysis device ofclaim 1, wherein the lid adhesive layer has a RMS roughness value below 3 μm.

54. The transdermal sampling and analysis device ofclaim 1, wherein the lid adhesive layer has a flow characteristic T_gbetween 0 and 50° C.

55. The transdermal sampling and analysis device ofclaim 1, wherein the sensing chamber has a volume less than 100 nl.

56. The transdermal sampling and analysis device ofclaim 1, wherein the sensing chamber has a volume of 10 nl.

57. The transdermal sampling and analysis device ofclaim 1, further comprising:

air vents coupled to the reservoir and configured to allow air contained in the reservoir to escape as the biological sample is obtained through the permeable barrier cells.

58. A system comprising:

a transdermal sampling and analysis device comprising:

a substrate having a first side;

a disruptor mounted on the first side of the substrate, wherein the disruptor has a resistance of about 5 Ohms to about 50 Ohms and is configured to generate a localized heat capable of altering the permeability characteristics of barrier cells of an organism to become permeable when a voltage is applied across the disruptor;

a reservoir on the first side of the transdermal sampling and analysis device, wherein the reservoir comprises:

a collection portion configured to collect and contain a biological sample that is obtained through the permeable barrier cells; and

a sensing chamber configured with a plurality of channels formed between a plurality of channel supports;

a biological sensing element comprising at least two sensing electrodes mounted on the first side of the substrate, wherein the biological sensing element is configured to determine the levels of an analyte in the biological sample;

a lid configured to enclose the reservoir and the at least two sensing electrodes within a volume formed in the reservoir;

a spacer disposed on top of the substrate; and

a lid adhesive layer adhering the lid to the spacer, wherein the lid adhesive layer has a hydrophilic wetting angle that is less than 40°,

wherein the sensing chamber is configured to contain the biological sample around the at least two sensing electrodes, wherein the biological sample is directed over the surface of the at least two sensing electrodes by the plurality of channels; and an applicator device comprising:

a housing configured to selectively engage the transdermal sampling and analysis device;

a processor, wherein the processor is coupled to the at least two sensing electrodes when the transdermal sampling and analysis device is engaged;

a display coupled to the processor;

a memory coupled to the processor; and

a voltage source coupled to the processor and for providing a voltage signal to the at least one disruptor when the transdermal sampling and analysis device is engaged, wherein the processor is configured to modify the voltage signal provided by the voltage source and apply the modified voltage signal to the at least one disruptor, and wherein the processor is configured to receive electrical signals from the at least two sensing electrodes and determine the levels of analyte present in the biological sample.

59. The system ofclaim 58, wherein the processor is configured to modify the voltage signal provided by the voltage source and apply the modified voltage signal to the at least one disruptor, wherein the voltage signal applied across the at least one disruptor is pulsed with a duty cycle of about 80 percent.

60. The system ofclaim 59, wherein a period of a completed duty cycle is 200 ms.

61. The system ofclaim 60, wherein the voltage signal is applied for 160 ms and turned off for 40 ms.

62. The system ofclaim 59, wherein the pulsed duty cycle has a frequency of about 1 Hz to 1 kHz.

63. The system ofclaim 59, wherein the pulsed duty cycle has a frequency of 5 Hz.

64. The system ofclaim 59, wherein the period of the pulses is about 0.5 sec to 5 sec.

65. The system ofclaim 59, wherein the voltage signal is applied for 3 sec to 20 sec.

66. The system ofclaim 59, wherein the voltage is applied for 3 sec to 10 sec.

67. The system ofclaim 58, wherein the display is configured to display the determined levels of analyte present in the biological sample.

68. The system ofclaim 58, wherein the applicator device further comprises a wireless transmitter configured to transmit the determined levels of analyte present in the biological sample to a remote computing device.

69. The system ofclaim 58, wherein the applicator device further comprises a communication port configured to transmit the determined levels of analyte present in the biological sample to a computing device via a wired connection.

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